2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections

ABSTRACT

Disclosed herein are 2′-spiro-nucleosides and derivatives thereof useful for treating a subject infected by hepatitis C virus or dengue virus.

PRIORITY

Priority is claimed to U.S. provisional patent application 61/417,946,filed on Nov. 30, 2010.

FIELD OF THE INVENTION

Disclosed herein are 2′-spiro-nucleosides and derivatives thereof usefulfor treating hepatitis C virus and dengue virus infections.

BACKGROUND

Hepatitis C virus (HCV) infection is a major health problem that leadsto chronic liver disease, such as cirrhosis and hepatocellularcarcinoma, in a substantial number of infected individuals, estimated tobe 2-15% of the world's population. According to the U.S. Center forDisease Control, there are an estimated 4.5 million infected people inthe United States alone. According to the World Health Organization,there are more than 200 million infected individuals worldwide, with atleast 3 to 4 million people being infected each year. Once infected,about 20% of people clear the virus, but the rest can harbor HCV therest of their lives. Ten to twenty percent of chronically infectedindividuals eventually develop liver-destroying cirrhosis or cancer. Theviral disease is transmitted parenterally by contaminated blood andblood products, contaminated needles, or sexually and vertically frominfected mothers or carrier mothers to their offspring. Currenttreatments for HCV infection, which are restricted to immunotherapy withrecombinant interferon-α alone or in combination with the nucleosideanalog ribavirin, are of limited clinical benefit. Moreover, there is noestablished vaccine for HCV. Consequently, there is an urgent need forimproved therapeutic agents that effectively combat chronic HCVinfection.

The HCV virion is an enveloped positive-strand RNA virus with a singleoligoribonucleotide genomic sequence of about 9600 bases which encodes apolyprotein of about 3,010 amino acids. The protein products of the HCVgene consist of the structural proteins C, E1, and E2, and thenon-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. Thenonstructural (NS) proteins are believed to provide the catalyticmachinery for viral replication. The NS3 protease releases NS5B, theRNA-dependent RNA polymerase from the polyprotein chain. HCV NS5Bpolymerase is required for the synthesis of a double-stranded RNA from asingle-stranded viral RNA that serves as a template in the replicationcycle of HCV. Therefore, NS5B polymerase is considered to be anessential component in the HCV replication complex (K. Ishi, et al,Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249:108-118). Inhibition of HCV NS5B polymerase prevents formation of thedouble-stranded HCV RNA and therefore constitutes an attractive approachto the development of HCV-specific antiviral therapies.

HCV belongs to a much larger family of viruses that share many commonfeatures.

Dengue viral infections are problematic in the tropical and subtropicalregions of the word. Shi et al. Top. Med. Chem. (2001) 7: 243-276. Thedengue virus (DENV) is transmitted to humans by certain mosquitos, andit is has been estimated that up to about 50 million infections occureach year. Parkinson et al. Future Med. Chem. (2010) 2(7): 1181-1203. Atthe present, there are no specific treatments for dengue viralinfections. Fagundes et al. Drug Development Research (2011) 72:480-500. DENV is comprised of ten proteins that includes threestructural proteins (C, prM, and E) and seven non-structural proteins(NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Of these ten proteins, onlyNS3 and NS5 are known to possess enzymatic activity. A desirable drugsubstance is one that interferes with the action or function of any oneof these ten viral proteins.

Flaviviridae Viruses

The Flaviviridae family of viruses comprises at least three distinctgenera: pestiviruses, which cause disease in cattle and pigs;flavivruses, which are the primary cause of diseases such as denguefever and yellow fever; and hepaciviruses, whose sole member is HCV. Theflavivirus genus includes more than 68 members separated into groups onthe basis of serological relatedness (Calisher et al., J. Gen. Virol,1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitisand hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe,D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia,Pa., 1996, Chapter 31, 931-959). Flaviviruses of global concern that areassociated with human disease include the Dengue Hemorrhagic Feverviruses (DHF), yellow fever virus, shock syndrome and Japaneseencephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6,251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., NewEng. J. Med, 1988, 319, 641-643).

The pestivirus genus includes bovine viral diarrhea virus (BVDV),classical swine fever virus (CSFV, also called hog cholera virus) andborder disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res.1992, 41, 53-98). Pestivirus infections of domesticated livestock(cattle, pigs and sheep) cause significant economic losses worldwide.BVDV causes mucosal disease in cattle and is of significant economicimportance to the livestock industry (Meyers, G. and Thiel, H. J.,Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv.Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been asextensively characterized as the animal pestiviruses. However,serological surveys indicate considerable pestivirus exposure in humans.

Pestiviruses and hepaciviruses are closely related virus groups withinthe Flaviviridae family. Other closely related viruses in this familyinclude the GB virus A, GB virus A-like agents, GB virus-B and GBvirus-C (also called hepatitis G virus, HGV). The hepacivirus group(hepatitis C virus; HCV) consists of a number of closely related butgenotypically distinguishable viruses that infect humans. There are atleast 6 HCV genotypes and more than 50 subtypes. Due to the similaritiesbetween pestiviruses and hepaciviruses, combined with the poor abilityof hepaciviruses to grow efficiently in cell culture, bovine viraldiarrhea virus (BVDV) is often used as a surrogate to study the HCVvirus.

The genetic organization of pestiviruses and hepaciviruses is verysimilar. These positive stranded RNA viruses possess a single large openreading frame (ORF) encoding all the viral proteins necessary for virusreplication. These proteins are expressed as a polyprotein that is co-and post-translationally processed by both cellular and virus-encodedproteinases to yield the mature viral proteins. The viral proteinsresponsible for the replication of the viral genome RNA are locatedwithin approximately the carboxy-terminal. Two-thirds of the ORF aretermed nonstructural (NS) proteins. The genetic organization andpolyprotein processing of the nonstructural protein portion of the ORFfor pestiviruses and hepaciviruses is very similar. For both thepestiviruses and hepaciviruses, the mature nonstructural (NS) proteins,in sequential order from the amino-terminus of the nonstructural proteincoding region to the carboxy-terminus of the ORF, consist of p7, NS2,NS3, NS4A, NS4B, NS5A, and NS5B.

The NS proteins of pestiviruses and hepaciviruses share sequence domainsthat are characteristic of specific protein functions. For example, theNS3 proteins of viruses in both groups possess amino acid sequencemotifs characteristic of serine proteinases and of helicases (Gorbalenyaet al., Nature, 1988, 333, 22; Bazan and Fletterick Virology, 1989, 171,637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17, 3889-3897).Similarly, the NS5B proteins of pestiviruses and hepaciviruses have themotifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. andDolja, V. V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).

The actual roles and functions of the NS proteins of pestiviruses andhepaciviruses in the lifecycle of the viruses are directly analogous. Inboth cases, the NS3 serine proteinase is responsible for all proteolyticprocessing of polyprotein precursors downstream of its position in theORF (Wiskerchen and Collett, Virology, 1991, 184, 341-350;Bartenschlager et al., J. Virol. 1993, 67, 3835-3844; Eckart et al.Biochem. Biophys. Res. Comm. 1993, 192, 399-406; Grakoui et al., J.Virol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl. Acad Sci. USA1993, 90, 10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675;Tome et al., J. Virol., 1993, 67, 4017-4026). The NS4A protein, in bothcases, acts as a cofactor with the NS3 serine protease (Bartenschlageret al., J. Virol. 1994, 68, 5045-5055; Failla et al., J. Virol. 1994,68, 3753-3760; Xu et al., J. Virol., 1997, 71:53 12-5322). The NS3protein of both viruses also functions as a helicase (Kim et al.,Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson,Arch. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J.Virol. 1995, 69, 1720-1726). Finally, the NS5B proteins of pestivirusesand hepaciviruses have the predicted RNA-directed RNA polymerasesactivity (Behrens et al., EMBO, 1996, 15, 12-22; Lechmann et al., J.Virol., 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm.1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol.,1998, 72, 9365-9369).

A number of potential molecular targets for drug development of directacting antivirals as anti-HCV therapeutics have now been identifiedincluding, but not limited to, the NS2-NS3 autoprotease, the N3protease, the N3 helicase and the NS5B polymerase. The RNA-dependent RNApolymerase is absolutely essential for replication of thesingle-stranded, positive sense, RNA genome and this enzyme has elicitedsignificant interest among medicinal chemists.

Inhibitors of HCV NS5B as potential therapies for HCV infection havebeen reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1,867-881; Walker, M. P. et al., Exp. Opin. Investigational Drugs, 2003,12, 1269-1280; Ni, Z-J., et al., Current Opinion in Drug Discovery andDevelopment, 2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinionin Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current DrugTargets-Infectious Disorders, 2003, 3, 207-219; Griffith, R. C., et al,Annual Reports in Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., etal., Infectious Disorders-Drug Targets, 2006, 6, 17-29. The potentialfor the emergence of resistant HCV strains and the need to identifyagents with broad genotype coverage supports the need for continuingefforts to identify novel and more effective nucleosides as HCV NS5Binhibitors.

Nucleoside inhibitors of NS5B polymerase can act either as a non-naturalsubstrate that results in chain termination or as a competitiveinhibitor which competes with nucleotide binding to the polymerase. Tofunction as a chain terminator the nucleoside analog must be taken up bythe cell and converted in vivo to a triphosphate to compete for thepolymerase nucleotide binding site. This conversion to the triphosphateis commonly mediated by cellular kinases which imparts additionalstructural requirements on a potential nucleoside polymerase inhibitor.Unfortunately, this limits the direct evaluation of nucleosides asinhibitors of HCV replication to cell-based assays capable of in situphosphorylation.

In some cases, the biological activity of a nucleoside is hampered byits poor substrate characteristics for one or more of the kinases neededto convert it to the active triphosphate form. Formation of themonophosphate by a nucleoside kinase is generally viewed as the ratelimiting step of the three phosphorylation events. To circumvent theneed for the initial phosphorylation step in the metabolism of anucleoside to the active triphosphate analog, the preparation of stablephosphate prodrugs has been reported. Nucleoside phosphoramidateprodrugs have been shown to be precursors of the active nucleosidetriphosphate and to inhibit viral replication when administered to viralinfected whole cells (McGuigan, C., et al., J. Med. Chem., 1996, 39,1748-1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990;Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299;Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg,E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20,1091-1098; Lee, W. A., et al., Antimicrobial Agents and Chemotherapy,2005, 49, 1898); US 2006/0241064; and WO 2007/095269.

Also limiting the utility of nucleosides as viable therapeutic agents istheir sometimes poor physicochemical and pharmacokinetic properties.These poor properties can limit the intestinal absorption of an agentand limit uptake into the target tissue or cell. To improve on theirproperties prodrugs of nucleosides have been employed. Additionalphosphate-containing prodrugs are also known: C. Schultz, Biorg. & Med.Chem. (2003) 11:885-898; C. McGuigan et al., Bioorg. & Med. Chem. Lett.(1994) 4(3): 427-430; C. Meier, Synlett (1998) 233-242; R. J. Jones etal., Antiviral Research (1995) 27: 1-17; G. J. Friis et al., Eur. J.Pharm. Sci. (1996) 4: 49-59; C. Meier Mini Reviews in MedicinalChemistry (2002) 2(3): 219-234; C. Perigaud et al., Advances inAntiviral Drug Design; DeClerq E., Ed.; Vol. 2; JAI Press, London, 1996.However, there is no general agreement as to which phosphate-containingprodrug provides for the best activity.

In an effort to improve treatment of HCV or DENV, it remains of vitalinterest to identify compounds capable of inhibiting the action of NS5Bpolymerase of HCV or of inhibiting the action or function of aparticular DENV protein.

SUMMARY

Disclosed herein is a compound or its stereoisomer or its salt or itsmetabolite or its deuteride thereof represented by formula I:

wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   where        -   R^(1a) is            -   i) hydrogen,            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) cycloalkyl,            -   iv) alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) an acyl,        -   p) a C₁₋₆-alkylene-oxy-acyl, and        -   q) a —C(O)—O-alkyl;    -   2) R² is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) azido,        -   d) cyano,        -   e) a C₁₋₆alkyl,        -   f) a vinyl, and        -   g) an ethynyl;    -   3) R³ is selected from among        -   a) hydrogen,        -   b) methyl, and        -   c) cyano,    -   4) Y is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) —OH,        -   d) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   e) —O(acyl),        -   f) —O(C₁₋₆-alkylene-oxy-acyl),        -   g) —O—C(O)—O-alkyl,        -   h) —NH₂,        -   i) —NH(acyl),        -   j) —NH—C(O)—O-alkyl, and        -   k) azido;    -   5) X is selected from among        -   a) —O—,        -   b) —S—,        -   c) —NH—,        -   d) —CH₂—,        -   e) >C═CH₂, and        -   f) —NH—C(O)—O-alkyl;    -   6)

is a four- or five-membered ring selected from among radicals a-orepresented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S— except for rings i and j,        -   iii) —S(O)— except for rings i and j,        -   iv) —S(O)₂— except for rings i and j, and        -   v) —NH— except for rings i and j,        -   vi) —N—,        -   vii) a methylene except for rings i and j,        -   viii) a methine, and        -   ix) a vinylidene except for rings i and j,    -   c) R⁴, R^(4′), R⁵, R^(5′), R⁶, R⁷, R⁸, R^(8′), R⁹, and R^(9′)        are independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) C₁₋₆alkyl,        -   iv) hydroxy,        -   v) alkoxy,        -   vi) cycloalkoxy,        -   vii) —O(acyl),        -   viii) —O(C₁₋₆-alkyleneoxyacyl),        -   ix) —O—C(O)—O-alkyl,        -   x) C₁₋₆alkylene-oxy(alkyl),        -   xi) alkenyl,        -   xii) ethynyl,        -   xiii) —NH₂,        -   xiv) —NH(alkyl),        -   xv) —NH(cycloalkyl),        -   xvi) heterocyclyl,        -   xvii) aryl, and        -   xviii) heteroaryl; and    -   7) B is selected from among B1, B2, and B3 represented by the        following structures:

-   -   where for B1 n is 0 or 1,        -   a) when n is 0,            is a double-bond and R¹⁰ is selected from among            -   i) —NH₂,            -   ii) —NH(alkyl),            -   iii) —NH(acyl),            -   iv) —NH—C(O)—O-alkyl,            -   v) -cycloheteroalkyl,            -   vi) -heteroaryl,            -   vii) —O(alkyl),            -   viii) —O(acyl),            -   ix) —O(C₁₋₆alkylene-oxyacyl), and            -   x) —O—C(O)—O-alkyl, or        -   b) when n is 1,            is a single-bond and R¹⁰ is selected from among            -   i) ═O,            -   ii) ═NH, and            -   iii) ═N(alkyl), and        -   c) independent of the value of n, R¹¹ and R¹² are            independently selected from among            -   i) hydrogen,            -   ii) halo,            -   iii) cyano,            -   iv) C₁₋₆alkyl,            -   v) C₂₋₅alkenyl, and            -   vi) C₂₋₅alkynyl,    -   where for B2,        -   a) R¹³ is selected from among            -   i) hydrogen,            -   ii) halo,            -   iii) cyano,            -   iv) —C(O)NH₂,            -   v) C₁₋₆alkyl,            -   vi) vinyl, and            -   vii) ethynyl,    -   where for B3 m is 0 or 1, and        is a single or double bond        -   a) when m is 0,            is a double-bond and R¹⁶ and R¹⁷ are independently            selected from among            -   i) hydrogen,            -   ii) —NH₂,            -   iii) —NH(alkyl),            -   iv) —NH(acyl),            -   iv) —NH—C(O)—O-alkyl,            -   v) -cycloheteroalkyl,            -   vi) —O(alkyl),            -   vii) —O(acyl),            -   viii) —O(C₁₋₆alkyleneoxyacyl), and            -   ix) —O—C(O)—O-alkyl,            -   x) —S(alkyl), or        -   b) when m is 1,            is a single-bond        -    b1) R¹⁶ is selected from among            -   i) ═O,            -   ii) ═NH, and            -   iii) ═N(alkyl), and        -    b2) R¹⁷ is selected from among            -   i) —NH₂,            -   ii) —NH(alkyl),            -   iii) —NH(acyl),            -   iv) —NH—C(O)—O-alkyl, and            -   v) -cycloheteroalkyl,        -   c) independent of the value of m, each bonding pair, W¹            W², W²            C, C            W⁴, W⁴            W³, and W³            W¹, contained in the five-membered ring comprises a single            or a double bond and            -   i) W¹ is O, S, N, or CR¹⁴,            -   ii) W² is N or CR¹⁵,            -   iii) W³ is C or N, and            -   iv) W⁴ is C or N        -   and where R¹⁴ and R¹⁵, if present, are independently            selected from among            -   i) hydrogen,            -   ii) halo,            -   iii) cyano,            -   iv) —C(O)NH₂,            -   iv) C₁₋₆alkyl,            -   vii) vinyl, and            -   viii) ethynyl.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “optional bond”means that the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “stereoisomer” has its plain and ordinary meaning.

The term “*” denotes the presence of a chiral center. Instances where“*” are not explicitly included in a radical does not necessarily meanthat the radical does not contain a chiral center.

The term “P*” means that the phosphorus atom is chiral and that it has acorresponding Cahn-Ingold-Prelog designation of “R” or “S” which havetheir accepted plain meanings. In some instances, aphosphorus-containing radical does not expressly include an “*” next tothe phosphorus atom, e.g., —P(O)(O(CH₂)₁₋₃OC(O)(alkyl))₂,—P(O)(O(CH₂)₁₋₃SC(O)(alkyl))₂, —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,—P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂. In these (and other) instances, it will beunderstood that chirality at phosphorus will be dictated by thesubstituent pattern. That is, when the substituents bound to phosphorusare the same, then achirality at phosphorus will exist, but when thesubstituents bound to the phosphorus are not the same, then chirality atphosphorus will exist.

The term “salts” or “salt thereof” as described herein, refers to acompound comprising a cation and an anion, which can prepared by anyprocess known to one of ordinary skill, e.g., by the protonation of aproton-accepting moiety and/or deprotonation of a proton-donatingmoiety. Alternatively, the salt can be prepared by a cation/anionmetathesis reaction. It should be noted that protonation of theproton-accepting moiety results in the formation of a cationic speciesin which the charge is balanced by the presence of a anion, whereasdeprotonation of the proton-donating moiety results in the formation ofan anionic species in which the charge is balanced by the presence of acation. It is understood that salt formation can occur under syntheticconditions, such as formation of pharmaceutically acceptable salts, orunder conditions formed in the body, in which case the correspondingcation or anion is one that is present in the body. Examples of commoncations found in the body include, but are not limited to: H⁺, Na⁺, K⁺,Mg²⁺, Ca²⁺, etc. Examples of common anions found in the body include,but are not limited to, Cl—, HCO₃ ⁻, CO₃ ²⁻, H₂PO₄ ⁻, HPO₄ ²⁻, etc.

The phrase “pharmaceutically acceptable salt” means a salt that ispharmaceutically acceptable. It is understood that the term“pharmaceutically acceptable salt” is encompassed by the expression“salt.” Examples of pharmaceutically acceptable salts include, but arenot limited to acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asglycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid,maleic acid, fumaric acid, tartaric acid, citric acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, salicylic acid, muconic acid, and thelike. Additional examples of anionic radicals of the pharmaceuticallyacceptable salt include but are not limited to: acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate (camphorsulfonate), carbonate, chloride, citrate,edetate, edisylate (1,2-ethanedisulfonate), estolate (lauryl sulfate),esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate),gluconate, glutamate, glycollylarsanilate(p-glycollamidophenylarsonate), hexylresorcinate, hydrabamine(N,N′-di(dehydroabietyl)ethylenediamine), hydroxynaphthoate, iodide,isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, malate,maleate, mandelate, mesylate, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, and teoclate(8-chlorotheophyllinate). Basic addition salts formed with the conjugatebases of any of the inorganic acids listed above, wherein the conjugatebases comprise a cationic component selected from among Li⁺, Na⁺, K⁺,Mg²⁺, Ca²⁺, Al³⁺, NH_(g)R′″_(4-g) ⁺, in which R′″ is a C₁₋₃ alkyl and gis a number selected from among 0, 1, 2, 3, or 4. Additional examples ofcationic radicals of the pharmaceutically acceptable salt, include butare not limited to: penzathine, phloroprocaine, pholine, piethanolamine,pthylenediamine, meglumine, and procaine.

The term “metabolite,” as described herein, refers to a compoundproduced in vivo after administration of a compound or its stereoisomeror its salt or its deuteride thereof represented by formula I to asubject in need thereof or as formed in vitro in an assay. Saidmetabolite may exist as a salt.

The term “deuteride,” as described herein, refers to a deuterated analogof the compound represented by formula I where a hydrogen atom isenriched with its ²H-isotope, i.e., deuterium (D). Deuteriumsubstitution can be partial or complete. Partial deuterium substitutionmeans that at least one hydrogen is substituted by at least onedeuterium.

The term “halo” or “halogen” as used herein, includes chloro, bromo,iodo and fluoro.

The term “alkyl” refers to an unbranched or branched chain, saturated,monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term“C_(1-M) alkyl” refers to an alkyl comprising 1 to M carbon atoms, whereM is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30.

The term “C₁₋₆alkyl” refers to an alkyl containing 1 to 6 carbon atoms.Examples of a C₁₋₆ alkyl group include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, t-pentyl, and hexyl.

The term “C₁₋₆-alkylene” refers to an alkylene radical containing 1 to 6carbon atoms. Examples of a C₁₋₆-alkylene include, but are not limitedto, a methylene (—CH₂—), ethylene (—CH₂CH₂—), methyl-ethylene(—CH(CH₃)CH₂—), propylene (—CH₂CH₂CH₂—), methyl-propylene(—CH(CH₃)CH₂CH₂— or —CH₂CH(CH₃)CH₂—), etc. It is understood that abranched C₁₋₆-alkylene, such as methyl-ethylene or methyl-propylene,contains a chiral center, in which case the individual stereoisomers arecontemplated. It is contemplated that a methylene may be substitutedwith one or two C₁₋₆alkyls.

The term “cycloalkyl” refers to an unsubstituted or substitutedcarbocycle, in which the carbocycle contains 3 to 10 carbon atoms;preferably 3 to 8 carbon atoms (i.e., a C₃₋₈-cycloalkyl); morepreferably 3 to 6 carbon atoms (i.e., a C₃₋₆-cycloalkyl). In theinstance of a substituted carbocycle containing 3 to 10, 3 to 8, or 3 to6 carbon atoms, the substituents are not to be counted for thecarbocycle carbon count. For instance, a cyclohexyl substituted with oneor more C₁₋₆-alkyl is still, within the meaning contemplated herein, aC₃₋₆-cycloalkyl. Examples of a C₃₋₆cycloalkyl include, but are notlimited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl,2-methyl-cyclobutyl, cyclopentyl, 2-methyl-cyclopentyl, cyclohexyl,2-methyl-cyclohexyl, etc.

The term “cycloalkylamino” refers to a unsubstituted or substitutedcarbocycle comprising an “amino” (—NH—) functional group. The carbocyclecontains 3 to 10 carbon atoms; preferably 3 to 8 carbon atoms (i.e., aC₃₋₈-cycloalkyl); more preferably 3 to 6 carbon atoms (i.e., aC₃₋₆-cycloalkyl). In the instance of a substituted carbocycle containing3 to 10, 3 to 8, or 3 to 6 carbon atoms, the substituents are not to becounted for the carbocycle carbon count. For instance, a cyclohexylsubstituted with one or more C₁₋₆-alkyl is still, within the meaningcontemplated herein, a C₃₋₆-cycloalkyl. Examples of aC₃₋₆cycloalkylamino (alternatively referred to as —NHC₃₋₆cycloalkyl)include, but are not limited to, cyclopropylamino,2-methyl-cyclopropylamino, cyclobutylamino, 2-methyl-cyclobutylamino,cyclopentylamino, 2-methyl-cyclopentylamino, cyclohexylamino,2-methyl-cyclohexylamino, etc. One of ordinary skill will know that saidcycloalkylaminos are derived from cycloalkylamines, i.e., cycloalkylssubstituted by an amine (—NH₂) functional group.

The term “alkoxy” refers to an —O-alkyl group or an —O-cycloalkyl group,wherein alkyl and cycloalkyl are as defined above. Examples of —O-alkylgroups include, but are not limited to, methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, etc. Examples of—O-cycloalkyl groups include, but are not limited to, —O-c-propyl,—O-c-butyl, —O-c-pentyl, —O-c-hexyl, etc.

The term “C₁₋₆-alkoxy” refers to an —O—C₁₋₆-alkyl group, wherein C₁₋₆alkyl is defined herein.

The term “C₃₋₆-cycloalkoxy” refers to an —O—C₃₋₆-cycloalkyl group

The term “C₁₋₆-alkylene-oxy” refers to an —O—C₁₋₆-alkylene group,wherein C₁₋₆-alkylene is defined as above. Examples of aC₁₋₆-alkylene-oxy include, but are not limited to, methylene-oxy(—CH₂O—), ethylene-oxy (—CH₂CH₂O—), methyl-ethylene-oxy (—CH(CH₃)CH₂O—),propylene-oxy (—CH₂CH₂CH₂O—), methyl-propylene-oxy (—CH(CH₃)CH₂CH₂O— or—CH₂CH(CH₃)CH₂O—), etc.

The terms “alkaryl” or “alkylaryl” refer to an alkylene group having 1to 10 carbon atoms with an aryl substituent, such as benzyl. The term“C₁₋₃alkaryl” refers to a C₁₋₃alkylene group with an aryl substituent.Benzyl is embraced by the term C₁₋₃alkaryl.

The term “—OC₁₋₃alkaryl” refers a oxygen (—O˜) bound to a C₁₋₃alkarylgroup. Benzyloxy (—OCH₂Ph) is embraced by the term —OC₁₋₃alkaryl.

The term “aryl,” as used herein, and unless otherwise specified, refersto substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl. Thearyl group can be substituted with one or more moieties selected fromamong alkyl, hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino,alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, and phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 3rd ed., John Wiley & Sons, 1999.

The term “heteroaryl” refers to an unsubstituted or substituted aromaticheterocycle containing carbon, hydrogen, and at least one of N, O, andS. Examples of heteroaryls include, but are not limited to, a pyrrole,an imidazole, a diazole, a triazole, a tetrazole, a furan, an oxazole,an indole, a thiazole, etc. Additional examples of heteroaryls can befound in T. L. Gilchrist, in “Heterocyclic Chemistry,” John Wiley &Sons, 1985. The heteroaryl group can be substituted with one or moremoieties selected from among alkyl, hydroxyl, F, Cl, Br, I, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,sulfate, phosphonic acid, phosphate, and phosphonate, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” 3rd ed., John Wiley & Sons,1999.

The term “heterocycle” or “heterocyclyl” refers to an unsubstituted orsubstituted radical containing carbon, hydrogen and at least one of N,O, and S. Examples of heterocycles, include, but are not limited to, anaziridine, an azetidine, a pyrrolidine, a piperidine, a piperazine, etc.Additional examples of heterocycles can be found in T. L. Gilchrist, in“Heterocyclic Chemistry,” John Wiley & Sons, 1985. The heterocycle canbe substituted with one or more moieties selected from among alkyl,hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, andphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in T. W. Greene and P.G. M. Wuts, “Protective Groups in Organic Synthesis,” 3rd ed., JohnWiley & Sons, 1999.

The terms “alk(heteroaryl)” and “alk(heterocyclyl)” refers to aC₁₋₆-alkylene group with a heteroaryl and heterocyclyl substituent,respectively.

The term “cycloheteroalkyl” refers to an unsubstituted or substitutedheterocycle, in which the heterocycle contains 2 to 9 carbon atoms;preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms.Examples of cycloheteroalkyls include, but are not limited to,aziridin-1-yl, aziridin-2-yl, N—C₁₋₃-alkyl-aziridin-2-yl, azetidinyl,azetidin-1-yl, N—C₁₋₃-alkyl-azetidin-m′-yl, pyrrolidin-m′-yl,pyrrolidin-1-yl, N—C₁₋₃-alkyl-pyrrolidin-m′-yl, piperidin-m′-yl,piperidin-1-yl, and N—C₁₋₃-alkyl-piperidin-m′-yl, where m′ is 2, 3, or 4depending on the cycloheteroalkyl. Specific examples ofN—C₁₋₃-alkyl-cycloheteroalkyls include, but are not limited to,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-2-yl, N-methyl-piperidin-3-yl, andN-methyl-piperidin-4-yl. In the instance of R¹⁰, R¹⁶, and R¹⁷, the pointof attachment between the cycloheteroalkyl ring carbon and the ringoccurs at any one of m′.

The term “acyl” refers to a substituent containing a carbonyl moiety anda non-carbonyl moiety and is meant to include an amino-acyl. Thecarbonyl moiety contains a double-bond between the carbonyl carbon and aheteroatom, where the heteroatom is selected from among O, N and S. Whenthe heteroatom is N, the N is substituted by a C₁₋₆. The non-carbonylmoiety is selected from straight, branched, and cyclic alkyl, whichincludes, but is not limited to, a straight, branched, or cyclic C₁₋₂₀alkyl, C₁₋₁₀ alkyl, or a C₁₋₆-alkyl; alkoxyalkyl, includingmethoxymethyl; aralkyl, including benzyl; aryloxyalkyl, such asphenoxymethyl; or aryl, including phenyl optionally substituted withhalogen (F, Cl, Br, I), hydroxyl, C₁ to C₄ alkyl, or C₁ to C₄ alkoxy,sulfonate esters, such as alkyl or aralkyl sulphonyl, includingmethanesulfonyl, the mono, di or triphosphate ester, trityl ormonomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least one arylgroup is present in the non-carbonyl moiety, it is preferred that thearyl group comprises a phenyl group.

The term “C₂₋₇acyl” refers to an acyl group in which the non-carbonylmoiety comprises a C₁₋₆alkyl. Examples of a C₂₋₇-acyl, include, but arenot limited to: —C(O)CH₃, —C(O)CH₂CH₃, —C(O)CH(CH₃)₂,—C(O)CH(CH₃)CH₂CH₃, —C(O)C(CH₃)₃, etc.

The term “aminoacyl” includes N,N-unsubstituted, N,N-monosubstituted,and N,N-disubstituted derivatives of naturally occurring and syntheticα, β γ or δ amino acyls, where the amino acyls are derived from aminoacids. The amino-nitrogen can be substituted or unsubstituted or existas a salt thereof. When the amino-nitrogen is substituted, the nitrogenis either mono- or di-substituted, where the substituent bound to theamino-nitrogen is a C₁₋₆alkyl or an alkaryl. In the instance of its usefor the compound of formula I, it is understood that an appropriate atom(O or N) is bound to the carbonyl carbon of the aminoacyl.

The term “amino acid” includes naturally occurring and synthetic α, β γor δ amino acids, and includes but is not limited to, amino acids foundin proteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. When the term amino acid is used, it is considered to be aspecific and independent disclosure of each of the esters of α, β γ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations.

The term “C₁₋₆-alkylene-oxy-acyl” refers to an —O—C₁₋₆-alkylene-acylgroup, wherein C₁₋₆-alkylene and acyl are defined as above. Examples ofa C₁₋₆-alkylene-oxy-acyl include, but are not limited to,methylene-oxy-acyl (—CH₂O—C(O)alkyl), ethylene-oxy-acyl(—CH₂CH₂O—C(O)alkyl), methyl-ethylene-oxy-acyl (—CH(CH₃)CH₂O—C(O)alkyl),propylene-oxy-acyl (—CH₂CH₂CH₂O—C(O)alkyl), methyl-propylene-oxy-acyl(—CH(CH₃)CH₂CH₂O—C(O)alkyl or —CH₂CH(CH₃)CH₂O—C(O)alkyl), etc. As theexpression “acyl” encompasses “aminoacyl,” further contemplated radicalsinclude but are not limited to C₁₋₆-alkyl-oxy-aminoacyl, where aminoacylis defined above.

The term “alkenyl” refers to an unsubstituted or a substitutedhydrocarbon chain radical having from 2 to 10 carbon atoms having one ormore olefinic double bonds. The term “C_(2-N) alkenyl” refers to analkenyl comprising 2 to N carbon atoms, where N is an integer having thefollowing values: 3, 4, 5, 6, 7, 8, 9, or 10. For example, the term“C₂₋₁₀ alkenyl” refers to an alkenyl comprising 2 to 10 carbon atoms.The term “C₂₋₄alkenyl” refers to an alkenyl comprising 2 to 4 carbonatoms. Examples include, but are not limited to, vinyl, 1-propenyl,2-propenyl (allyl) or 2-butenyl (crotyl). It is understood that thealkenyl or C_(2-N)-alkenyl can be substituted with one or more radicalsselected from among alkyl, halo, alkoxy, aryloxy, nitro, and cyano.

The term “vinyl,” which is embraced by the term “C₂₋₄alkenyl,” refers to—CR′═CR″R′″, where R′, R″, and R′″ are independently selected from amonghydrogen, C₁₋₆-alkyl, halo, and C₁₋₆-alkoxy. Examples of a vinylinclude, but are not limited to, ethenyl (—CH═CH₂), 2-bromo-ethenyl(—CH═CHBr), etc.

The term “ethynyl,” as used herein, refers to —C≡CR′, where R′ isselected from among hydrogen, C₁₋₆-alkyl, halo, and C₁₋₆-alkoxide.

The term “methine,” as used herein, refers to the radical —CR′═, whereR′ is selected from among hydrogen, C₁₋₆alkyl, halo, and C₁₋₆-alkoxide.

The term “vinylidene,” as used herein, refers to >C═CRR′, where R and R′are independently selected from among hydrogen, C₁₋₆-alkyl, halo, andC₁₋₆-alkoxide.

The expressions —P(O)(OH)₂, —P(O)(OH)—OP(O)(OH)₂, and—P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂, refer to mono- (P₁), di- (P₂), andtri- (P₃) phosphate radicals, respectively.

The P₁, P₂, and P₃ phosphate radicals may be introduced at the 5′-OH ofa nucleoside compound either by synthetic means in the lab or byenzymatic (or metabolic) means in a cell or biological fluid (either invivo or in vitro). It is understood that the acidities of the hydroxyl(—OH) substituents vary and that salts of the phosphate radicals arepossible.

The term “—P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c))” or “phosphoramidate”as used herein is represented by the following structure:

where R^(1a), R^(1b), and R^(1c) are as defined above. Examples ofphosphoramidate moieties are described in U.S. Pat. No. 7,964,580. Itwill be understood that the ˜NHCH*(R^(1b))C(O)OR^(1c) fragment can bederived from an amino acid, which is defined above.

Under the Summary, certain definitions related to R¹, 1)l), and Y, 4)d),include the expressions “—P*(O)(OR^(1c))˜” (see R¹, 1)l)) and “—O˜” (seeY, 4)d)). It is understood that when R¹ is “—P*(O)(OR^(1c))˜” and Y is“—O˜” or when Y is “—O˜” and R¹ is “—P(O)(OR^(1c))˜”, then compound Ihas the structure shown on the left, where the R¹ and Y substituents areidentified on the right:

It is understood that use of the expression “cyclophosphate” or“cyclic-phosphate” is meant to embrace the left-hand structure. Theseexpressions likewise have the same meanings when recited as definitionsfor certain embodiments and aspects of those embodiments.

The term “a 1,3,2-dioxaphosphinane-2-oxide,” as used herein isrepresented by an unsubstituted form (j1) or a substituted form (j2), asrepresented by the following structures:

where R_(n) is selected from among hydroxy, an alkyl, a hydroxyalkyl, anaryloxide, an aryl, such as phenyl, a heteroaryl, such as pyridinyl,where the aryl and the heteroaryl can be substituted by 1-3 substituentsindependently selected from among an alkyl, an alkoxy, and a halo. Apreferred R_(n) is pyridinyl which can be substituted by 1-3substituents independently selected from among a C₁₋₆alkyl, aC₁₋₆-alkoxy, and a halo.

The term “aryloxide,” or “aryloxy” as used herein, and unless otherwisespecified, refers to substituted or unsubstituted phenoxide (PhO—),p-phenyl-phenoxide (p-Ph-PhO—), or naphthoxide, preferably the termaryloxide refers to substituted or unsubstituted phenoxide. Thearyloxide group can be substituted with one or more moieties selectedfrom among hydroxyl, F, Cl, Br, I, —C(O)(C₁₋₆alkyl), —C(O)O(C₁₋₆alkyl),amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonicacid, sulfate, phosphonic acid, phosphate, and phosphonate, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” 3rd ed., John Wiley & Sons,1999.

The term “4H-benzo[d][1,3,2]dioxaphosphine-2-oxide,” as used herein isrepresented by an unsubstituted form (k1) or a substituted form (k2), asrepresented by the following structures:

where R_(n) and R′_(n), where R_(n) is hydrogen and one alkyl radical,or two alkyl radicals independent of one another, and R′_(n) is one,two, or three radicals selected from among alkyl, alkoxy, aryloxy, andhalo. Preferably, R′_(n) is one, two, or three radicals selected fromamong a C₁₋₆alkyl, a C₁₋₆, alkoxy, and a halo. More preferably, R′_(n)is one radical selected from among a C₁₋₆-akyl, a C₁₋₆-alkoxy, and ahalo.

In the structure B3, as a possible radical for B, the language “eachbonding pair, W¹

W², W²

C, C

W⁴, W⁴

W³, and W³

W¹, contained in the five-membered ring comprises a single or a doublebond” is presented above.

In the event that resolution problems or printing errors might obscurethe pictoral representation of B3, it is contemplated that there existsa bonding configuration represented by “

” between each one of W¹

W², W²

C, C

W⁴, W⁴

W³, and W³

W¹, within the five-membered ring framework, where “

” is understood to be a single- or double-bond. It is not contemplatedthat all bonding pairs contained in the five-membered ring therein areall double bonds or all single bonds. Rather, it is contemplated thatwhen a certain definitional requirement is selected, then the bondingarrangement of the five-membered ring satisfies Hückel's rule, i.e., thetotal number of pi-bond and lone-pair electrons for the selectedradicals is 6. For example, when W¹ is O or S, W² is CR¹⁵, W³ is C, andW⁴ is C (see I-3-12 or I-3-13), then the contemplated structure is:

Formula I is recited above. Implicit to formula I is the exclusion ofcompounds disclosed in B. R. Babu et al. Org. Biomol. Chem. (2003) 1:3514-3526, whether said compounds are explicitly or implicitly disclosedtherein. For instance, the compounds identified there as 9b, 14b, 21,and 27, are not contemplated to be within the scope of formula I (aswell as formula I-1 presented below)

However, these compounds, as well as derivatives embraced by formula I,are contemplated for treating a subject infected by HCV or DENV and arecontemplated for compositions useful for treating a subject infected byHCV or DENV, as explained in further detail below. The compoundnumbering for compounds 9b, 14b, 21, and 27 is as found in Babu et al.It should be noted that compounds 21 and 27 are exemplified herein withthe numbering here of 36 and 32, respectively.

The term “effective amount” as used herein means an amount required toreduce symptoms of the disease in a subject.

The term “subject,” as used herein means a mammal.

The term “medicament,” as used herein means a substance used in a methodof treatment and/or prophylaxis of a subject in need thereof.

The term “preparation” or “dosage form” is intended to include bothsolid and liquid formulations of the active compound and one skilled inthe art will appreciate that an active ingredient can exist in differentpreparations depending on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is used toprepare a pharmaceutical composition, and is generally safe, non-toxicand neither biologically nor otherwise undesirable, and includesexcipients that are acceptable for veterinary use as well as humanpharmaceutical use.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired clinical results. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. “Treatment” is an intervention performed with the intentionof preventing the development or altering the pathology of a disorder.The term “treatment” of an HCV infection, as used herein, also includestreatment or prophylaxis of a disease or a condition associated with ormediated by HCV infection, or the clinical symptoms thereof.

The term “protecting group” which is derived from a “protectingcompound,” has its plain and ordinary meaning, i.e., at least oneprotecting or blocking group is bound to at least one functional group(e.g., —OH, —NH₂, etc.) that allows chemical modification of at leastone other functional group. Examples of protecting groups, include, butare not limited to, benzoyl, acetyl, phenyl-substituted benzoyl,tetrahydropyranyl, trityl, DMT (4,4′-dimethoxytrityl), MMT(4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl)group, thiopixyl (9-phenylthioxanthen-9-yl) or9-(p-methoxyphenyl)xanthine-9-yl (MOX), etc.; C(O)-alkyl, C(O)Ph,C(O)aryl, C(O)O(C₁₋₆alkyl), C(O)O(C₁₋₆alkylene)aryl (e.g., —C(O)OCH₂Ph),C(O)Oaryl, CH₂O-alkyl, CH₂O-aryl, SO₂-alkyl, SO₂-aryl, a protectinggroup comprising at least one silicon atom, such as,tert-butyldimethylsilyl, tert-butyldiphenylsilyl,Si(C₁₋₆alkyl)₂OSi(C₁₋₆alkyl)₂OH, such as, —Si(^(i)Pr)₂OSi(^(i)Pr)₂OH or˜OSi(^(i)Pr)₂OSi(^(i)Pr)₂O˜. Additional examples are disclosed in e.g.,Protective Groups in Organic Synthesis, 3^(nd) ed. T. W. Greene and P.G. M. Wuts, John Wiley & Sons, New York, N.Y., 1999).

The term “leaving group” (“LG”) as used herein, has its plain andordinary meaning for one of ordinary skill in this art. Examples ofleaving groups include, but are not limited to: halogen (Cl, Br, or I);tosylate, mesylate, triflate, acetate, etc.

Embodiments

A first embodiment is directed to a compound or its stereoisomer or itssalt or its metabolite or its deuteride thereof represented by formulaI-1

wherein R¹, R², Y, R³,

X, R¹⁰, R¹¹, R¹², n, and

have the meanings described above.

A first aspect of the first embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-1

wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   vi) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) azido, and        -   d) cyano;    -   3) R³ is selected from among        -   a) hydrogen,        -   b) methyl, and        -   c) cyano,    -   4) Y is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) —OH,        -   d) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   e) —O(C₂₋₇acyl),        -   f) —O(aminoacyl),        -   g) —O(C₁₋₆-alkylene-oxy-acyl),        -   h) —O—C(O)—O—C₁₋₆alkyl,        -   i) —NH₂,        -   j) —NH(C₂₋₇acyl),        -   k) —NH(aminoacyl),        -   l) —NH—C(O)—O—C₁₋₆alkyl and        -   m) azido;    -   5) X is selected from among        -   a) —O— and        -   b) —S—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene,    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) C₁₋₆alkyl        -   iv) hydroxy,        -   v) alkoxy,        -   vi) cycloalkoxy,        -   vii) —O(acyl),        -   viii) —O(C₁₋₆-alkyleneoxyacyl),        -   ix) —O—C(O)—O-alkyl,        -   x) C₁₋₆alkylene-oxy(alkyl),        -   xi) alkenyl,        -   xii) ethynyl,        -   xiii) —NH₂,        -   xiv) —NH(alkyl),        -   xv) —NH(cycloalkyl),        -   xvi) heterocyclyl,        -   xvii) aryl, and        -   xviii) heteroaryl; and    -   7a) n is 0,        is a double-bond and R¹⁰ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(acyl),        -   iv) —NH—C(O)—O-alkyl,        -   v) -cycloheteroalkyl,        -   vi) -heteroaryl,        -   vii) —O(alkyl),        -   viii) —O(acyl),        -   ix) —O(C₁₋₆alkylene-oxyacyl), and    -   7b) n is 1,        is a single-bond and R¹⁰ is selected from among        -   i) ═O,        -   ii) ═NH, and        -   iii) ═N(alkyl); and    -   7c) independent of the value of n, R¹¹ and R¹² are independently        selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) C₁₋₆alkyl,        -   v) C₂₋₅alkenyl, and        -   vi) C₂₋₅alkynyl.

A second aspect of the first embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-1

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—,        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene,    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo, and        -   iii) C₁₋₆alkyl; and    -   7a) n is 0,        is a double-bond and R¹⁰ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl), and        -   iv) —NH—C(O)—O—C₁₋₆alkyl, or    -   7b) n is 1,        is a single-bond and R¹⁰ is selected from among        -   i) ═O and        -   ii) ═N(alkyl), and    -   7c) independent of the value of n, R¹¹ and R¹² are independently        selected from among        -   i) hydrogen,        -   ii) halo,        -   iv) C₁₋₆alkyl, and        -   v) C₂₋₄alkenyl.

A third aspect of the first embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-1

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   vi) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—,    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7a) n is 0,        is a double-bond and R¹⁰ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl), and        -   iv) —NH—C(O)—O—C₁₋₆alkyl, or    -   7b) n is 1,        is a single-bond and R¹⁰ is selected from among        -   i) ═O and        -   ii) ═N(alkyl), and    -   7c) independent of the value of n, R¹¹ and R¹² are independently        selected from among        -   i) hydrogen,        -   ii) halo,        -   iv) C₁₋₆alkyl, and        -   v) C₂₋₄alkenyl.

A fourth aspect of the first embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-1

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl);    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,and f represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—,    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7a) n is 0,        is a double-bond and R¹⁰ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl), and        -   iv) —NH—C(O)—O—C₁₋₆alkyl, or    -   7b) n is 1,        is a single-bond and R¹⁰ is selected from among        -   i) ═O and        -   ii) ═N(alkyl), and    -   7c) independent of the value of n, R¹¹ and R¹² are independently        selected from among        -   i) hydrogen,        -   ii) halo,        -   iv) C₁₋₆alkyl, and        -   v) C₂₋₄alkenyl.

A second embodiment is directed to a compound or its stereoisomer or itssalt or its metabolite or its deuteride thereof represented by formulaI-2

wherein

wherein R¹, R², Y, R³,

X, and R¹³ have the meanings described above.

A first aspect of the second embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-2 wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) azido, and        -   d) cyano;    -   3) R³ is selected from among        -   a) hydrogen,        -   b) methyl, and        -   c) cyano,    -   4) Y is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) —OH,        -   d) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   e) —O(C₂₋₇acyl),        -   f) —O(aminoacyl),        -   g) —O(C₁₋₆-alkylene-oxy-acyl),        -   h) —O—C(O)—O—C₁₋₆alkyl,        -   i) —NH₂,        -   j) —NH(C₂₋₇acyl),        -   k) —NH(aminoacyl),        -   l) —NH—C(O)—O—C₁₋₆alkyl, and        -   m) azido;    -   5) X is selected from among        -   a) —O— and        -   b) —S—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene,    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) C₁₋₆alkyl        -   iv) hydroxy,        -   v) alkoxy,        -   vi) cycloalkoxy,        -   vii) —O(acyl),        -   viii) —O(C₁₋₆-alkyleneoxyacyl),        -   ix) —O—C(O)—O-alkyl,        -   x) C₁₋₆alkylene-oxy(alkyl),        -   xi) alkenyl,        -   xii) ethynyl,        -   xiii) —NH₂,        -   xiv) —NH(alkyl),        -   xv) —NH(cycloalkyl),        -   xvi) heterocyclyl,        -   xvii) aryl, and        -   xviii) heteroaryl; and    -   7) R¹³ is hydrogen.

A second aspect of the second embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-2

wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene,    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) C₁₋₆alkyl; and    -   7) R¹³ is hydrogen.

A third aspect of the second embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-2

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—, and    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7) R¹³ is hydrogen.

A fourth aspect of the second embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-2

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) an C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl);    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,and f represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—, and    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7) R¹³ is hydrogen.

A third embodiment is directed to a compound or its stereoisomer or itssalt or its metabolite or its deuteride thereof represented by formulaI-3

wherein R¹, R², Y, R³,

X, W¹, W², W³, W⁴, R¹⁶, R¹⁷, m, and

have the meanings described above.

A first aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) azido, and        -   d) cyano;    -   3) R³ is selected from among        -   a) hydrogen,        -   b) methyl, and        -   c) cyano;    -   4) Y is selected from among        -   a) hydrogen,        -   b) fluoro,        -   c) —OH,        -   d) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   e) —O(C₂₋₇acyl),        -   f) —O(aminoacyl),        -   g) —O(C₁₋₆-alkylene-oxy-acyl),        -   h) —O—C(O)—O—C₁₋₆alkyl,        -   i) —NH₂,        -   j) —NH(C₂₋₇acyl),        -   k) —NH(aminoacyl),        -   l) —NH—C(O)—O—C₁₋₆alkyl, and        -   m) azido;    -   5) X is selected from among        -   a) —O— and        -   b) —S—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene, and    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) C₁₋₆alkyl        -   iv) hydroxy,        -   v) alkoxy,        -   vi) cycloalkoxy,        -   vii) —O(acyl),        -   viii) —O(C₁₋₆-alkyleneoxyacyl),        -   ix) —O—C(O)—O-alkyl,        -   x) C₁₋₆alkylene-oxy(alkyl),        -   xi) alkenyl,        -   xii) ethynyl,        -   xiii) —NH₂,        -   xiv) —NH(alkyl),        -   xv) —NH(cycloalkyl),        -   xvi) heterocyclyl,        -   xvii) aryl, and        -   xviii) heteroaryl; and    -   7a) m is 0,        is a double-bond and R¹⁶ and R¹⁷ are independently selected from        among        -   i) hydrogen,        -   ii) —NH₂,        -   iii) —NH(C₁₋₆alkyl),        -   iv) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl,        -   v) -cycloheteroalkyl,        -   vi) —O(C₁₋₆alkyl),        -   vii) —O(C₂₋₇acyl),        -   viii) —O(C₁₋₆alkyleneoxyacyl),        -   ix) —O—C(O)—O—C₁₋₆alkyl,        -   x) —S(C₁₋₆alkyl), and        -   xi) —OC₁₋₃alkaryl,    -   7b) m is 1,        is a single-bond and    -    b1) R¹⁶ is selected from among        -   i) ═O,        -   ii) ═NH, and        -   iii) ═N(C₁₋₆alkyl), and    -    b2) R¹⁷ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl, and        -   v) -cycloheteroalkyl, and    -   7c) independent of the value of m, each bonding pair, W¹        W², W²        C, C        W⁴, W⁴        W³, and W³        W¹, contained in the five-membered ring comprises a single or a        double bond and        -   i) W¹ is O, S, N, or CR¹⁴,        -   ii) W² is N or CR¹⁵,        -   iii) W³ is C or N, and        -   iv) W⁴ is C or N, and    -   where R¹⁴ and R¹⁵, if present, are independently selected from        among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A second aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3

wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,f, g, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,    -   b) D is selected from among        -   i) —O—,        -   ii) —S—,        -   iii) —S(O)—,        -   iv) —S(O)₂—, and        -   v) —NH—,        -   vi) a methylene, and        -   vii) a vinylidene,    -   c) R⁴, R⁵, R⁸, and R⁹ are independently selected from among        -   i) hydrogen,        -   ii) halo, and        -   iii) C₁₋₆alkyl; and    -   7a) m is 0,        is a double-bond and R¹⁶ and R¹⁷ are independently selected from        among        -   i) hydrogen,        -   ii) —NH₂,        -   iii) —NH(C₁₋₆alkyl),        -   iv) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl,        -   v) -cycloheteroalkyl,        -   vi) —O(C₁₋₆alkyl),        -   vii) —O(C₂₋₇acyl),        -   viii) —O(C₁₋₆alkyleneoxyacyl),        -   ix) —O—C(O)—O—C₁₋₆alkyl,        -   x) —S(C₁₋₆alkyl), and        -   xi) —OC₁₋₃alkaryl,    -   7b) m is 1,        is a single-bond and    -    b1) R¹⁶ is selected from among        -   i) ═O,        -   ii) ═NH, and        -   iii) ═N(C₁₋₆alkyl), and    -    b2) R¹⁷ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl, and        -   v) -cycloheteroalkyl, and    -   7c) independent of the value of m, each bonding pair, W¹        W², W²        C, C        W⁴, W⁴        W³, and W³        W¹, contained in the five-membered ring comprises a single or a        double bond and        -   i) W¹ is O, S, N, or CR¹⁴,        -   ii) W² is N or CR¹⁵,        -   iii) W³ is C or N, and        -   iv) W⁴ is C or N, and    -   where R¹⁴ and R¹⁵, if present, are independently selected from        among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A third aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3

-   -   wherein    -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen,            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl,            -   iv) C₁₋₃alkaryl, or            -   v) alk(heteroaryl), and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   p) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   q) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl),        -   e) —O(C₁₋₆-alkylene-oxy-acyl), and        -   f) —O—C(O)—O—C₁₋₆alkyl;    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e, fg, and h, represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—,    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7a) m is 0,        is a double-bond and R¹⁶ and R¹⁷ are independently selected from        among        -   i) hydrogen,        -   ii) —NH₂,        -   iii) —NH(C₁₋₆alkyl),        -   iv) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl,        -   v) -cycloheteroalkyl,        -   vi) —O(C₁₋₆alkyl),        -   vii) —O(C₂₋₇acyl),        -   viii) —O(C₁₋₆alkyleneoxyacyl),        -   ix) —O—C(O)—O—C₁₋₆alkyl,        -   x) —S(C₁₋₆alkyl), and        -   xi) —OC₁₋₃alkaryl,    -   7b) m is 1,        is a single-bond and    -    b1) R¹⁶ is selected from among        -   i) ═O,        -   ii) ═NH, and        -   iii) ═N(C₁₋₆alkyl), and    -    b2) R¹⁷ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl, and        -   v) -cycloheteroalkyl,    -   7c) independent of the value of m, each bonding pair, W¹        W², W²        C, C        W⁴, W⁴        W³, and W³        W¹, contained in the five-membered ring comprises a single or a        double bond and        -   i) W¹ is O, S, N, or CR¹⁴,        -   ii) W² is N or CR¹⁵,        -   iii) W³ is C or N, and        -   iv) W⁴ is C or N, and    -   where R¹⁴ and R¹⁵, if present, are independently selected from        among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A fourth aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3

wherein

-   -   1) R¹ is selected from among        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   iv) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) an C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-C₂₋₇acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl;    -   2) R² is hydrogen;    -   3) R³ is hydrogen;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl);    -   5) X is —O—;    -   6)

is a four- or five-membered ring selected from among radicals c, d, e,and f represented by the following structures

where * represents the point of attachment to the 2′-carbon and where

-   -   a) A is —O—,    -   b) D is —O— or —CH₂—,    -   c) R⁴, R⁵, R⁸, and R⁹ are each hydrogen; and    -   7a) m is 0,        is a double-bond and R¹⁶ and R¹⁷ are independently selected from        among        -   i) hydrogen,        -   ii) —NH₂,        -   iii) —NH(C₁₋₆alkyl),        -   iv) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl,        -   v) -cycloheteroalkyl,        -   vi) —O(C₁₋₆alkyl),        -   vii) —O(C₂₋₇acyl),        -   viii) —O(C₁₋₆alkyleneoxyacyl),        -   ix) —O—C(O)—O—C₁₋₆alkyl,        -   x) —S(C₁₋₆alkyl), and        -   xi) —OC₁₋₃alkaryl    -   7b) m is 1,        is a single-bond and    -    1) R¹⁶ is selected from among        -   i) ═O,        -   ii) ═NH, and        -   iii) ═N(C₁₋₆alkyl), and    -    b2) R¹⁷ is selected from among        -   i) —NH₂,        -   ii) —NH(C₁₋₆alkyl),        -   iii) —NH(C₂₋₇acyl),        -   iv) —NH—C(O)—O—C₁₋₆alkyl, and        -   v) -cycloheteroalkyl,    -   7c) independent of the value of m, each bonding pair, W¹        W², W²        C, C        W⁴, W⁴        W³, and W³        W¹, contained in the five-membered ring comprises a single or a        double bond and        -   i) W¹ is O, S, N, or CR¹⁴,        -   ii) W² is N or CR¹⁵,        -   iii) W³ is C or N, and        -   iv) W⁴ is C or N, and    -   where R¹⁴ and R¹⁵, if present, are independently selected from        among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A fifth aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-1

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1a)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl, and        -   j) an aminoacyl; and    -   2) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl); and    -   3)

is selected from among

where * represents the point of attachment to the 2′-carbon; and

-   -   4a) m is 0,        is a double-bond        -   4a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) -cycloalkylamino,            -   v) —O(C₁₋₆alkyl),            -   vi) —O(C₂₋₇acyl),            -   vii) —O(C₁₋₆alkyleneoxyacyl), and            -   viii) —O—C(O)—O—C₁₋₆alkyl,            -   ix) —S(C₁₋₆alkyl), and            -   x) —OC₁₋₃alkaryl, and        -   4a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂, and            -   iii) —NH(C₁₋₆alkyl), or    -   4b) m is 1,        is a single-bond        -   4b1) R¹⁶ is ═O; and        -   4b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl).

A sixth aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-1

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) phenyl,            -   iii) p-fluorophenyl,            -   iv) p-chlorophenyl,            -   v) p-bromophenyl, or            -   vi) naphthyl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   d) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   e) —P(O)(OH)—O—P(O)(OH)₂,        -   f) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   g) a C₂₋₇acyl, and        -   h) an aminoacyl; and    -   2) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl); and    -   3)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   4a) m is 0,        is a double-bond        -   4a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) -cycloalkylamino,            -   v) —O(C₁₋₆alkyl),            -   vi) —O(C₂₋₇acyl),            -   vii) —O(C₁₋₆alkyleneoxyacyl), and            -   viii) —O—C(O)—O—C₁₋₆alkyl,            -   ix) —S(C₁₋₆alkyl), and            -   x) —OC₁₋₃alkaryl, and        -   4a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iiii) —NH(C₁₋₆alkyl), or    -   4b) m is 1,        is a single-bond        -   4b1) R¹⁶ is ═O and        -   4b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl).

A seventh aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-1

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) phenyl,            -   iii) p-fluorophenyl,            -   iv) p-chlorophenyl,            -   v) p-bromophenyl, or            -   vi) naphthyl,        -   R^(b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   d) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   e) —P(O)(OH)—O—P(O)(OH)₂,        -   f) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   g) a C₂₋₇acyl, and        -   h) an aminoacyl; and    -   2) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl); and    -   3)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   4a) m is 0,        is a double-bond        -   4a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) -cycloalkylamino,            -   v) —O(C₁₋₆alkyl),            -   vi) —O(C₂₋₇acyl),            -   vii) —S(C₁₋₆alkyl), and            -   viii) —OC₁₋₃alkaryl, and        -   4a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂, and            -   iii) —NH(C₁₋₆alkyl), or    -   4b) m is 1,        is a single-bond        -   4b1) R¹⁶ is ═O and        -   4b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl).

An eighth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-1

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) phenyl,            -   iii) p-fluorophenyl,            -   iv) p-chlorophenyl,            -   v) p-bromophenyl, or            -   vi) naphtyl,        -   R^(b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   vi) C₁₋₃alkaryl,        -   d) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   e) —P(O)(OH)—O—P(O)(OH)₂,        -   f) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   g) a C₂₋₇acyl, and        -   h) an aminoacyl; and    -   2) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl), and        -   d) —O(aminoacyl); and    -   3)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   4a) m is 0,        is a double-bond        -   4a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   4a2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl), or        -   4a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   4a4) R¹⁷ is hydrogen, or    -   4b) m is 1,        is a single-bond        -   4b1) R¹⁶ is ═O and        -   4b2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl).

A ninth aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-2

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) phenyl,            -   iii) p-fluorophenyl,            -   iv) p-chlorophenyl,            -   v) p-bromophenyl, or            -   vi) naphthyl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   d) —P(O)(OH)—O—P(O)(OH)₂,        -   e) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   f) a C₂₋₇acyl, and        -   g) an aminoacyl; and    -   2)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   3a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino and        -   3a2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl), or        -   3a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino and        -   3a4) R¹⁷ is hydrogen, or    -   3b) m is 1,        is a single-bond        -   3b1) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂.

A tenth aspect of the third embodiment is directed to a compound or itsstereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-3

-   -   wherein    -   1) R^(1a) is        -   a) hydrogen,        -   b) phenyl,        -   c) p-fluorophenyl,        -   d) p-chlorophenyl,        -   e) p-bromophenyl, or        -   f) naphthyl, and    -   2) R^(1c) is        -   a) hydrogen        -   b) C₁₋₆alkyl,        -   c) C₃₋₆cycloalkyl, or        -   d) C₁₋₃alkaryl;    -   3)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   4a) m is 0,        is a double-bond        -   4a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   4a2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl), or        -   4a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   4a4) R¹⁷ is hydrogen, or    -   4b) m is 1,        is a single-bond        -   4b1) R¹⁶ is ═O and        -   4b2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl).

An eleventh aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-4

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen,            -   ii) phenyl,            -   iii) p-fluorophenyl,            -   iv) p-chlorophenyl,            -   v) p-bromophenyl, or            -   vi) naphthyl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) C₁₋₆alkyl,            -   iii) C₃₋₆cycloalkyl, or            -   iv) C₁₋₃alkaryl,        -   d) —P(O)(OH)—O—P(O)(OH)₂,        -   e) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   f) a C₂₋₇acyl, and        -   g) an aminoacyl; and    -   2a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl), or        -   3a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino and        -   3a4) R¹⁷ is hydrogen, or    -   2b) m is 1,        is a single-bond        -   3b1) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl).

A twelfth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-5

-   -   wherein    -   1) R^(1a) is        -   a) hydrogen,        -   b) phenyl, or        -   c) naphthyl, and    -   2) R^(1c) is        -   a) hydrogen        -   b) C₁₋₆alkyl,        -   c) C₃₋₆cycloalkyl, or        -   d) C₁₋₃alkaryl; and    -   3a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl), or        -   3a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a4) R¹⁷ is hydrogen, or    -   3b) m is 1,        is a single-bond        -   3b1) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl).

A thirteenth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-5

-   -   wherein    -   1) R^(1a) is        -   a) hydrogen,        -   b) phenyl, or        -   c) naphthyl, and    -   2) R^(1c) is        -   a) hydrogen        -   b) C₁₋₆alkyl,        -   c) C₃₋₆cycloalkyl, or        -   d) C₁₋₃alkaryl; and    -   3a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a2) R¹⁷ is —NH₂, or        -   3a3) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —NH(C₁₋₆alkyl), —S(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a4) R¹⁷ is hydrogen, or    -   3b) m is 1,        is a single-bond        -   3b) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂.

A fourteenth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-5

-   -   wherein    -   1) R^(1a) is        -   a) hydrogen,        -   b) phenyl, or        -   c) naphthyl, and    -   2) R^(1c) is        -   a) hydrogen        -   b) C₁₋₆alkyl,        -   c) C₃₋₆cycloalkyl, or        -   d) C₁₋₃alkaryl; and    -   3a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl) or —OC₁₋₃alkaryl, and        -   3a2) R¹⁷ is —NH₂, or        -   3a3) R¹⁶ is —NH₂, and        -   3a4) R¹⁷ is hydrogen, or    -   3b) m is 1,        is a single-bond        -   3b1) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂.

A fifteenth aspect of the third embodiment is directed to a compound orits salt thereof represented by formula I-3-6

-   -   wherein    -   1) R¹ is hydrogen, —P(O)(OH)₂, —P(O)(OH)—O—P(O)(OH)₂, or        —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂.

A sixteenth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-7

-   -   1) R^(1c) is        -   a) hydrogen        -   b) C₁₋₆alkyl,        -   c) C₃₋₆cycloalkyl, or        -   d) C₁₋₃alkaryl;    -   2)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   3a) m is 0,        is a double-bond        -   3a1) R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl),            —NH(C₁₋₆alkyl), or -cycloalkylamino, and        -   3a2) R¹⁷ is —NH₂, or        -   3b1) R¹⁶ is —NH₂, —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,            —NH(C₁₋₆alkyl), —S(C₁₋₆alkyl), or -cycloalkylamino and        -   3b2) R¹⁷ is hydrogen, or    -   3b) m is 1,        is a single-bond        -   3b1) R¹⁶ is ═O and        -   3b2) R¹⁷ is —NH₂ or —NH(C₁₋₆alkyl).

A seventeenth aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-8

wherein B′ is selected from among B5, B6, B7, B8, B9, and B10represented by the following structures

and R¹, R², Y, R³,

X, R¹⁴, R¹⁵, R¹⁶, R¹⁷, m, and

have the meanings described above.

An eighteenth aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-8,

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   vi) —C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) an C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(acyl), and        -   d) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and        -   7a) m is 0,            is a double-bond and R¹⁶ and R¹⁷ are independently selected            from among            -   i) hydrogen,            -   ii) —NH₂,            -   iii) —NH(alkyl),            -   iv) —NH(acyl),            -   iv) —NH—C(O)—O-alkyl,            -   v) -cycloheteroalkyl,            -   vi) —O(alkyl),            -   vii) —O(acyl),            -   viii) —O(C₁₋₆alkyleneoxyacyl),            -   ix) —O—C(O)—O-alkyl,            -   x) —S(C₁₋₆alkyl), or            -   xi) —OC₁₋₃alkaryl,        -   7b) m is 1,            is a single-bond and        -    b1) R¹⁶ is selected from among            -   i) ═O,            -   ii) ═NH,            -   iii) ═N(alkyl), and        -    b2) R¹⁷ is selected from among            -   i) —NH₂,            -   ii) —NH(alkyl),            -   iii) —NH(acyl),            -   iv) —NH—C(O)—O-alkyl, and            -   v) -cycloheteroalkyl,        -   7c) independent of the value of m, R¹⁴ and R¹⁵, if present,            are independently selected from among            -   i) hydrogen,            -   ii) halo,            -   iii) cyano,            -   iv) —C(O)NH₂,            -   iv) C₁₋₆alkyl,            -   vii) vinyl, and            -   viii) ethynyl.

A nineteenth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-8 wherein

-   -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen,            -   ii) alkyl,            -   iii) cycloalkyl, or            -   vi) —C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) an C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(acyl), and        -   d) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —NH—C(O)—O—C₁₋₆alkyl,            -   v) -cycloheteroalkyl,            -   vi) —O(C₁₋₆alkyl),            -   vii) —O(C₂₋₇acyl),            -   viii) —O(C₁₋₆alkyleneoxyacyl),            -   ix) —O—C(O)—O—C₁₋₆alkyl,            -   x) —S(C₁₋₆alkyl), and            -   xi) —OC₁₋₃alkaryl, and        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂,            -   iii) —NH(C₁₋₆alkyl),            -   iv) —NH(C₂₋₇acyl), and            -   v) —NH—C(O)—O—C₁₋₆alkyl, or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl), and            -   iii) —NH(C₂₋₇acyl), and    -   7c) independent of the value of m, R¹⁴ and R¹⁵, if present, are        independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A twentieth aspect of the third embodiment is directed to a compound orits stereoisomer or its salt or its metabolite or its deuteride thereofrepresented by formula I-3-8 wherein

-   -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P(O)(O(CH₂)₁₋₃OC(O)O(C₁₋₆alkyl))₂,        -   d) —P(O)(O(CH₂)₁₋₃OC(O)(C₁₋₆alkyl))₂,        -   e) —P(O)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl))₂,        -   f) —P(O)(O(CH₂)₁₋₃OCH₂(aryl))₂,        -   g) —P(O)(O(CH₂)₁₋₃SCH₂(aryl))₂,        -   h) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   vi) —C₁₋₃alkaryl,        -   i) —P*(O)(NH(alkaryl)(O(CH₂)₁₋₃SC(O)(C₁₋₆alkyl)),        -   j) a 1,3,2-dioxaphosphinane-2-oxide,        -   k) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   l) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   m) —P(O)(OH)—O—P(O)(OH)₂,        -   n) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   o) a C₂₋₇acyl,        -   p) an aminoacyl,        -   q) a C₁₋₆-alkylene-oxy-acyl, and        -   r) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   d) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl), and            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl,        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂,            -   iii) —NH(C₁₋₆alkyl),            -   iv) —NH(C₂₋₇acyl), and            -   v) —NH—C(O)—O—C₁₋₆alkyl, or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R⁷ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl), and            -   iii) —NH(C₂₋₇acyl), and    -   7c) independent of the value of m, R¹⁴ and R¹⁵, if present, are        independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A twenty-first aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-8 wherein

-   -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   e) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl), and            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl,        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl) and    -   7c) independent of the value of m, R¹⁴ and R¹⁵, if present, are        independently selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A twenty-second aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-9

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   d) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl), and            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl),            -   ix) —OC₁₋₃alkaryl, and        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O; and        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl) and    -   7c) independent of the value of m, R¹⁴ and R¹⁵ are independently        selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A twenty-third aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-10

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   e) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl), and            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl,        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl) and        -   7c) independent of the value of m, R¹⁴ is selected from            among            -   i) hydrogen,            -   ii) halo,            -   iii) cyano,            -   iv) —C(O)NH₂,            -   iv) C₁₋₆alkyl,            -   vii) vinyl, and            -   viii) ethynyl.

A twenty-fourth aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-11

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   e) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl),            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl, and        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl).

A twenty-fifth aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-12

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   e) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl),            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl,        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl) and    -   7c) independent of the value of m, R¹⁵ is selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.

A twenty-sixth aspect of the third embodiment is directed to a compoundor its stereoisomer or its salt or its metabolite or its deuteridethereof represented by formula I-3-13

-   -   wherein    -   1) R¹ is selected from among:        -   a) hydrogen,        -   b) —P(O)(OH)₂,        -   c) —P*(O)(OR^(1a))(NHCHR^(1b)C(O)OR^(1c)),        -   wherein        -   R^(1a) is            -   i) hydrogen or            -   ii) aryl,        -   R^(1b) is            -   i) hydrogen or            -   ii) C₁₋₆alkyl, and        -   R^(1c) is            -   i) hydrogen            -   ii) alkyl,            -   iii) cycloalkyl, or            -   iv) —C₁₋₃ alkaryl,        -   d) a 1,3,2-dioxaphosphinane-2-oxide,        -   e) a 4H-benzo[d][1,3,2]dioxaphosphinine-2-oxide,        -   f) —P*(O)(OR^(1c))˜, when Y is —O˜, where R^(1c) is defined            above,        -   g) —P(O)(OH)—O—P(O)(OH)₂,        -   h) —P(O)(OH)—O—P(O)(OH)—O—P(O)(OH)₂,        -   i) a C₂₋₇acyl,        -   j) an aminoacyl,        -   k) a C₁₋₆-alkylene-oxy-acyl, and        -   l) a —C(O)—O—C₁₋₆alkyl,    -   2) R² is hydrogen;    -   3) R³ is hydrogen or cyano;    -   4) Y is selected from among        -   a) —OH,        -   b) —O˜, when R¹ is —P(O)(OR^(1c))˜, where R^(1c) is defined            above,        -   c) —O(C₂₋₇acyl),        -   d) —O(aminoacyl), and        -   e) —O(C₁₋₆-alkylene-oxyC₂₋₇acyl);    -   5) X is —O—;    -   6)

is selected from among

-   -   where * represents the point of attachment to the 2′-carbon; and    -   7a) m is 0,        is a double-bond,        -   7a1) R¹⁶ is selected from among            -   i) —NH₂,            -   ii) —NH(C₁₋₆alkyl),            -   iii) —NH(C₂₋₇acyl),            -   iv) —O(C₁₋₆alkyl),            -   v) —O(C₂₋₇acyl),            -   vi) —O(C₁₋₆alkyleneoxyacyl),            -   vii) —O—C(O)—O—C₁₋₆alkyl,            -   viii) —S(C₁₋₆alkyl), and            -   ix) —OC₁₋₃alkaryl,        -   7a2) R¹⁷ is selected from among            -   i) hydrogen,            -   ii) —NH₂ and            -   iii) —NH(C₁₋₆alkyl), or    -   7b) m is 1,        is a single-bond,        -   7b1) R¹⁶ is ═O;        -   7b2) R¹⁷ is selected from among            -   i) —NH₂ and            -   ii) —NH(C₁₋₆alkyl) and    -   7c) independent of the value of m, R¹⁵ is selected from among        -   i) hydrogen,        -   ii) halo,        -   iii) cyano,        -   iv) —C(O)NH₂,        -   iv) C₁₋₆alkyl,        -   vii) vinyl, and        -   viii) ethynyl.            Dosage, Administration, and Use

In the embodiments of this section, the expression “Compound I” is meantto encompass a compound or its stereoisomer or its salt or itsmetabolite or its deuteride thereof represented by formula Inotwithstanding the excluded subject matter found in the Definitions.

A fourth embodiment is directed to a composition comprising compound I.

A first aspect of the fourth embodiment is directed to a composition fortreating a subject infected with any one of hepatitis C virus, hepatitisB virus, Hepatitis A virus, West Nile virus, yellow fever virus, denguevirus, rhinovirus, polio virus, bovine viral diarrhea virus, Japaneseencephalitis virus, or those viruses belonging to the groups ofPestiviruses, hepaciviruses, or flavaviruses, said compositioncomprising an effective amount of compound I.

A second aspect of the fourth embodiment is directed to a compositionfor treating a subject infected with a hepatitis C virus, whichcomprises an effective amount of compound I and optionally apharmaceutically acceptable medium.

A third aspect of the fourth embodiment is directed to a composition fortreating a subject infected with a dengue virus, which comprises aneffective amount of compound I and optionally a pharmaceuticallyacceptable medium.

A fourth aspect of the fourth embodiment is directed to a compositionfor treating a subject infected with any one of a hepatitis B virus, aHepatitis A virus, a West Nile virus, a yellow fever virus, arhinovirus, polio virus, a bovine viral diarrhea virus, and a Japaneseencephalitis virus, which comprises an effective amount of compound Iand a pharmaceutically acceptable medium.

A fifth aspect of the fourth embodiment is directed to a composition fortreating a subject infected with a hepatitis C virus, which comprises aneffective amount of compound I and a pharmaceutically acceptable medium.

A sixth aspect of the fourth embodiment is directed to a composition fortreating a subject infected with a dengue virus, which comprises aneffective amount of compound I and a pharmaceutically acceptable medium.

A seventh aspect of the fourth embodiment is directed to a compositionfor treating a subject infected with a virus from any one of virusesbelonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses,which comprises an effective amount of compound I and a pharmaceuticallyacceptable medium.

Compound I may be independently formulated in a wide variety of oraladministration dosage forms and carriers. Oral administration can be inthe form of tablets, coated tablets, hard and soft gelatin capsules,solutions, emulsions, syrups, or suspensions. Compound I is efficaciouswhen administered by suppository administration, among other routes ofadministration. The most convenient manner of administration isgenerally oral using a convenient daily dosing regimen which can beadjusted according to the severity of the disease and the patient'sresponse to the antiviral medication.

Compound I together with one or more conventional excipients, carriers,or diluents, may be placed into the form of pharmaceutical compositionsand unit dosages.

The pharmaceutical compositions and unit dosage forms may be comprisedof conventional ingredients in conventional proportions, with or withoutadditional active compounds and the unit dosage forms may contain anysuitable effective amount of the active ingredient commensurate with theintended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as suspensions, emulsions, or filled capsules for oral use;or in the form of suppositories for rectal or vaginal administration. Atypical preparation will contain from about 5% to about 95% activecompound or compounds (w/w).

As noted above, the term “effective amount” as used herein means anamount required to reduce symptoms of the disease in a subject. The dosewill be adjusted to the individual requirements in each particular case.That dosage can vary within wide limits depending upon numerous factorssuch as the severity of the disease to be treated, the age and generalhealth condition of the patient, other medicaments with which thepatient is being treated, the route and form of administration and thepreferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.001 and about 10g, including all values in between, such as 0.001, 0.0025, 0.005,0.0075, 0.01, 0.025, 0.050, 0.075, 0.1, 0.125, 0.150, 0.175, 0.2, 0.25,0.3, 0.4, 0.5, 0.6, 0.7 0.75, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per day should beappropriate in monotherapy and/or in combination therapy. A particulardaily dosage is between about 0.01 and about 1 g per day, including allincremental values of 0.01 g (i.e., 10 mg) in between, a preferred dailydosage about 0.01 and about 0.8 g per day, more preferably about 0.01and about 0.6 g per day, and most preferably about 0.01 and about 0.25 gper day, each of which including all incremental values of 0.01 g inbetween. Generally, treatment is initiated with a large initial “loadingdose” to rapidly reduce or eliminate the virus following by a decreasingthe dose to a level sufficient to prevent resurgence of the infection.One of ordinary skill in treating diseases described herein will beable, without undue experimentation and in reliance on knowledge,experience and the disclosures of this application, to ascertain aeffective amount of the compound disclosed herein for a given diseaseand patient.

Compound I can be administered alone but will generally be administeredin admixture with one or more suitable pharmaceutical excipients,diluents or carriers selected with regard to the intended route ofadministration and standard pharmaceutical practice.

Solid form preparations include, for example, powders, tablets, pills,capsules, suppositories, and dispersible granules. A solid carrier maybe one or more substances which may also act as diluents, flavoringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like. Examples of solid formulations are exemplified in EP 0524579;US 2002/0142050; US 2004/0224917; US 2005/0048116; US 2005/0058710; US2006/0034937; US 2006/0057196; US 2006/0188570; US 2007/0026073; US2007/0059360; US 2007/0077295; US 2007/0099902; US 2008/0014228; U.S.Pat. Nos. 6,267,985; 6,294,192; 6,383,471; 6,395,300; 6,569,463;6,635,278; 6,645,528; 6,923,988; 6,932,983; 7,060,294; and 7,462,608.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs and aqueoussuspensions. These include solid form preparations which are intended tobe converted to liquid form preparations shortly before use. Examples ofliquid formulation are exemplified in U.S. Pat. Nos. 3,994,974;5,695,784; and 6,977,257. Emulsions may be prepared in solutions, forexample, in aqueous propylene glycol solutions or may containemulsifying agents such as lecithin, sorbitan monooleate, or acacia.Aqueous suspensions can be prepared by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well known suspending agents.

Compound I may be independently formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

Compound I may be independently formulated for vaginal administration.Pessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate. Certain of these formulations may also be used inconjunction with a condom with or without a spermicidal agent.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering compositions containing the compounds contemplated hereinunstable or compromising their therapeutic activity.

Additionally, compound I may be independently formulated in conjunctionwith liposomes, micelles, or complexed to or entrapped in a proteinmatrix, such as albumin. As to liposomes, it is contemplated that thecompound I can be formulated in a manner as disclosed in U.S. Pat. Nos.4,797,285; 5,013,556; 5,077,056; 5,077,057; 5,154,930; 5,192,549;5,213,804; 5,225,212; 5,277,914; 5,316,771; 5,376,380; 5,549,910;5,567,434; 5,736,155; 5,827,533; 5,882,679; 5,891,468; 6,060,080;6,132,763; 6,143,321; 6,180,134; 6,200,598; 6,214,375; 6,224,903;6,296,870; 6,653,455; 6,680,068; 6,726,925; 7,060,689; and 7,070,801. Asto micelles, it is contemplated that compound I can be formulated in amanner as disclosed in U.S. Pat. Nos. 5,145,684 and 5,091,188. As to aprotein matrix, it is contemplated that compound I can be complexed toor entrapped in a protein matrix as disclosed in any one of U.S. Pat.Nos. 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868;6,753,006; and 7,820,788.

A fifth embodiment is directed to a use of compound I for themanufacture of a medicament for the treatment of any condition theresult of an infection by any one of the following viral agents:hepatitis C virus, West Nile virus, yellow fever virus, dengue virus,rhinovirus, polio virus, hepatitis A virus, bovine viral diarrhea virusand Japanese encephalitis virus.

A first aspect of the fifth embodiment is directed to a use of compoundI for the manufacture of a medicament for the treatment of a hepatitis Cvirus.

A second aspect of the fifth embodiment is directed to a use of compoundI for the manufacture of a medicament for the treatment of a denguevirus.

A third aspect of the fifth embodiment is directed to a use of compoundI for the manufacture of a medicament for the treatment of any conditionthe result of an infection by any one of the following viral agents: aWest Nile virus, a yellow fever virus, a rhinovirus, a polio virus, ahepatitis A virus, a bovine viral diarrhea virus, and a Japaneseencephalitis virus.

A fourth aspect of the fifth embodiment is directed to a use of compoundI for the manufacture of a medicament for the treatment of any conditionthe result of an infection by a viral agent from any one of virusesbelonging to the groups of Pestiviruses, hepaciviruses, or flavaviruses.

As noted above, the term “medicament” means a substance used in a methodof treatment and/or prophylaxis of a subject in need thereof, whereinthe substance includes, but is not limited to, a composition, aformulation, a dosage form, and the like, comprising compound I. It iscontemplated that the use of any of compound I for the manufacture of amedicament for the treatment of any of the antiviral conditionsdisclosed herein, either alone or in combination with another compounddisclosed herein. A medicament includes, but is not limited to, any oneof the compositions contemplated by the fourth embodiment disclosedherein.

A sixth embodiment is directed to a method of treating a subjectinfected with any one of a hepatitis C virus, a West Nile virus, ayellow fever virus, a degue virus, a rhinovirus, a polio virus, ahepatitis A virus, a bovine viral diarrhea virus, a Japaneseencephalitis virus or those viruses belonging to the groups ofPestiviruses, hepaciviruses, or flavaviruses, said method comprisingadministering an effective amount of compound I to the subject.

A first aspect of the sixth embodiment is directed to a method oftreating a subject infected with a hepatitis C virus, said methodcomprising administering an effective amount of compound I to thesubject.

A second aspect of the sixth embodiment is directed to a method oftreating a subject infected with a dengue virus, said method comprisingadministering an effective amount of compound I to the subject. A thirdaspect of the sixth embodiment is directed to a method of treating asubject injected with any one of a West Nile virus, a yellow fevervirus, a rhinovirus, a polio virus, a hepatitis A virus, a bovine viraldiarrhea virus, a Japanese encephalitis virus or those viruses belongingto the groups of Pestiviruses, hepaciviruses, or flavaviruses, saidmethod comprising administering an effective amount of compound I to thesubject.

It is intended that a subject in need thereof is one that has anycondition the result of an infection by any of the viral agentsdisclosed herein, which includes, but is not limited to, a hepatitis Cvirus, a West Nile virus, a yellow fever virus, a dengue virus, arhinovirus, a polio virus, a hepatitis A virus, a bovine viral diarrheavirus or a Japanese encephalitis virus; flaviviridae viruses orpestiviruses or hepaciviruses or a viral agent causing symptomsequivalent or comparable to any of the above-listed viruses.

As noted above, the term “subject” means a mammal, which includes, butis not limited to, cattle, pigs, sheep, buffalo, llama, dogs, cats,mice, rats, monkeys, and humans, preferably the subject is a human. Itis contemplated that in the method of treating a subject thereof of theninth embodiment can be any of the compounds contemplated herein, eitheralone or in combination with another compound disclosed herein.

Therapeutic efficacy can be ascertained from tests of liver functionincluding, but not limited to protein levels such as serum proteins(e.g., albumin, clotting factors, alkaline phosphatase,aminotransferases (e.g., alanine transaminase, aspartate transaminase),5′-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis ofbilirubin, synthesis of cholesterol, and synthesis of bile acids; aliver metabolic function, including, but not limited to, carbohydratemetabolism, amino acid and ammonia metabolism. Alternatively thetherapeutic effectiveness may be monitored by measuring HCV-RNA. Theresults of these tests will allow the dose to be optimized.

A fourth aspect of the sixth embodiment is directed to a method oftreating a subject infected with hepatitis C virus or a subject infectedwith a dengue virus, said method comprising administering to the subjectan effective amount of compound I and an effective amount of anotherantiviral agent; wherein the administration is concurrent oralternative. It is understood that the time between alternativeadministration can range between 1-24 hours, which includes anysub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours. It will be understoodthat the effective amount of compound I and the effective amount ofanother antiviral agent can be formulated in the same dosage form orformulated in separate dosage forms.

A fifth aspect of the sixth embodiment comprises adding to the3′-terminus of an HCV RNA strand or a DENV RNA strand a radical or itssalt thereof represented by

where

is the point of attachment to the 3′-terminus. It is understood thataddition of said compound to the nascent RNA strand will prevent orsubstantially increase the likelihood that propagation of the RNA strandhaving said compound added thereto will come to an end.

A seventh aspect of the sixth embodiment comprises increasing anintracellular concentration of a triphosphate (P₃) compound or its saltthereof represented by

in a cell infected with HCV or DENV.

When compound I is administered in combination with another antiviralagent the activity may be increased over the activity exhibited forcompound I alone. When the treatment is combination therapy, suchadministration may be concurrent or sequential with respect to that ofthe nucleoside derivatives. “Concurrent administration” as used hereinthus includes administration of the agents at the same time or atdifferent times. Administration of two or more agents at the same timecan be achieved by a single formulation containing two or more activeingredients or by substantially simultaneous administration of two ormore dosage forms with a single active agent.

It will be understood that references herein to treatment extend toprophylaxis as well as to the treatment of existing conditions.

Examples of “another antiviral agent” include, but are not limited to:HCV NS3 protease inhibitors (see EP 1881001, US 2003/0187018, US2005/0267018, US 2003/0119752, US 2003/0187018, US 2005/0090432, US2009/0291902, US 2005/0267018, US 2005/0267018, US 2011/0237621, US2009/0281141, US 2009/0105302, US 2009/0062311, US 2009/0281140, US2007/0054842, US 2008/0108617, and US 2008/0108617); HCV NS5B Inhibitors(see US 2004/0229840, US 2005/0154056, US 2005/0098125, US 2006/0194749,US 2006/0241064, US 2006/0293306, US 2006/0040890, US 2006/0040927, US2006/0166964, US 2007/0275947, U.S. Pat. No. 6,784,166, US 2007/0275930,US 2002/0147160, US 2002/0147160, US 2003/0176433, US 2004/0024190, US2005/0043390, US 2005/0026160, US 2004/0171570, US 2005/0130923, US2008/0146788, US 2007/0123484, US 2007/0024277, US 2007/0004669, US2004/0142989, US 2004/0142993, US 2006/0004063, US 2006/0234962, US2007/0231318, US 2007/0142380, WO 2004/096210, US 2007/0135363, WO2005/103045, US 2008/0021047, US 2007/0265222, US 2006/0046983, US2008/0280842, WO 2006065590, US 2006/0287300, WO 2007039142, WO2007039145, US 2007/0232645, US 2007/0232627, WO 2007088148, WO2007092000, and US 2010/0234316); HCV NS4 Inhibitors (see US2005/0228013 and US 2007/0265262); HCV NS5A Inhibitors (see US2006/0276511, US 2007/0155716, US 2008/0182863, US 2009/0156595, and US2008/0182863); Toll-like receptor agonists (see US 2007/0197478); andother inhibitors (see US 2003/0207922, US 2006/0094706, US 2006/0122154,US 2005/0069522, US 2005/0096364, US 2005/0069522, US 2005/0096364, andUS 2005/0215614); PSI-6130 (U.S. Pat. No. 7,429,572); RG7128 (U.S. Pat.No. 7,754,699); Compound A (disclosed in US 2010/0081628, see alsocompound 19a (PSI-938) and 19b disclosed in the same application, whichare individual diastereomers of compound A); PSI-7977 (U.S. Pat. No.7,964,580, claim 8) and PSI-7976 (disclosed in US 2010/0016251 and US2010/0298257 (Ser. No. 12/783,680) (PSI-7977 (Sp-4) and PSI-7976(Rp-4)); PSI-353661 (disclosed in US 2010/0279973, see compound 11);telaprevir (also known as VX-950, which is disclosed in US2010/0015090); boceprevir (disclosed in US 2006/0276405); BMS-790052(disclosed in US 2008/0050336, see also US 2009/0041716); ITMN-191(disclosed in US 2009/0269305 at Example 62-1); ANA-598 (shown below andidentified as compound 3i in F. Ruebasam et al. Biorg. Med. Chem. Lett.(2008) 18: 3616-3621; and TMC435 (formerly known as TMC435350).

The antiviral agents can be formulated in a manner known to one ofordinary skill. The respective patent documents provide guidance for therespective formulations. The preferred dosage forms of the antiviralagents are those that are approved by the FDA. However, not to belimited, contemplated dosage forms of the antiviral agents arecontemplated as follows: RG7128 (500 mg, 1000 mg, or 1500 mg); CompoundA (5 mg to 1000 mg and values inbetween); PSI-7977 (100 mg, 200 mg, or400 mg); A dosage form for VX-950 is disclosed in McHutchison et al. N.Engl. J. Med. (2009) 360(18): 1827-1838; see also WO 2009/038663;Boceprevir (WO 2009/038663).

Additional examples of “another antiviral agent” and contemplateddosages are identified in the following table.

Clinical Drug Name Drug Category Company Phase Dosage RG7128 PolymeraseRoche in Phase I 500 mg Inhibitor collaboration with BID, 100 mgPharmasset BID RG7227 Protease Roche in Phase I 100 mg TID, Inhibitorcollaboration with 200 mg TID Pharmasset Telaprevir Protease VertexPhase II N/A (VX-950) Inhibitor VX-222 Polymerase Vertex Phase II N/AInhibitor BMS 790052 NS5a Inhibitor Bristol-Myers Squibb Phase II 60 mgonce a day or 600 mg twice a day BMS 65032 Protease Bristol-Myers SquibbPhase II 60 mg once a Inhibitor day or 600 mg twice a day BMS-824393NS5A Inhibitor Bristol-Myers Squibb Phase I N/A INX-189 HCV PolymeraseInhibitex Phase I from 3 mg to Inhibitor 100 mg, once a day PSI-938Polymerase Pharmasset Phase I 300 mg once Inhibitor a day PPI-461 NS5AInhibitor Presidio Phase I four single Pharmaceuticals doses followed bya 5-day, once-a-day dose IDX375 Polymerase Idenix Phase I 25 mg onceInhibitor daily (QD), 50 mg QD, 100 mg QD, 200 mg QD, or 200 mg twice aday ABT-072 Polymerase Abbott Phase I N/A Inhibitor Clemizole NS4BInhibitor Eiger Phase I N/A BioPharmaceuticals MK-3281 Polymerase MerckPhase I N/A Inhibitor PSI-7851 Polymerase Pharmasset Phase I 50 mg,Inhibitor 100 mg, 200 mg, or 400 mg ABT-450 Protease Abbott/Enanta PhaseI N/A HCV Inhibitor VX-813 Protease Vertex Phase I N/A Inhibitor PHX1766Protease Phenomix Phase I 400 mg BID Inhibitor or 800 mg BID ABT-333Polymerase Abbott Phase I N/A Inhibitor VX-916 HCV Polymerase VertexPhase I N/A Inhibitor RG7128 Polymerase Pharmasset/Genentech Phase I 500or Inhibitor 100 mg BID VX-500 HCV Protease Vertex Phase I N/A InhibitorFilibuvir HCV Polymerase Pfizer Phase II 200, 300, or (PF- Inhibitor0500 mg 00868554) BID (twice a day) ACH-1625 Protease Achillion Phase II200 or 600 Inhibitor mg GS-9256 Protease Gilead Phase II N/A InhibitorBI 201335 Protease Boehringer Ingelheim Phase II 240 mg Inhibitor Pharma(once-a-day) or 240 mg (twice-a-day) VX-222 Polymerase Vertex Phase II250, 500, or Inhibitor 750 mg twice-a-day; 1500 mg once-a-day RG7227Protease InterMune/Genentech Phase II N/A (Danoprevir) Inhibitor ANA598Polymerase Anadys Phase II First day 800 Inhibitor Pharmaceuticals mgBID, followed by 200 or 400 mg twice daily Vaniprevir HCV Protease MerckPhase II 300 or 600 (MK-7009) Inhibitor mg twice a day; 300 or 600 mgonce-a-day A-832 NS5A Inhibitor ArrowTherapeutics Phase II N/A GS 9190Polymerase Gilead Phase II N/A Inhibitor VX-759 Polymerase Vertex PhaseII 400 mg TID, Inhibitor 800 mg BID, or 800 mg TID SCH900518 ProteaseSchering/Merck Phase II N/A (Narlaprevir) Inhibitor BI 207127 PolymeraseBoehringer Ingelheim Phase II N/A Inhibitor Pharma PSI-7977 PolymerasePharmasset Phase IIa 100, 200, or Inhibitor 400 mg once-a-day TMC435Protease Medivir/Tibotec Phase IIa N/A Inhibitor BMS 791325 PolymeraseBristol-Myers Squibb Phase IIa N/A Inhibitor BMS 650032 ProteaseBristol-Myers Squibb Phase IIa/b N/A Inhibitor BMS 790052 NS5a InhibitorBristol-Myers Squibb Phase IIb N/A Boceprevir Protease Schering PhaseIII 800 mg three (SCH Inhibitor times a day 503034) Telaprevir ProteaseVertex Phase III 750 mg (VX 950) Inhibitor every 8 hours; 1125 mg doseevery 12 hours; BMS-824393 Type Unknown Bristol-Myers Squibb Phase I N/ASCY-635 Cyclophilin SCYNEXIS Phase I up to 900 Inhibitor mg/day ANA773TLR Agonist Anadys Phase I 800, 1200, Pharmaceuticals 1600, or 200 mgevery other day CYT107 Immunomodulator Cytheris Phase I N/A CF102 A3ARAgonist CAN-FITE Phase I N/A IMO-2125 TLR9 Agonist Idera Phase I N/APharmaceuticals Bavituximab Anti-Phospholipid Peregrine Phase I N/A(formerly Therapy Tarvacin) NOV-205 Immunomodulator Novelos TherapeuticsPhase I N/A SD-101 TLR9 Agonist Dynavax Phase Ib N/A Miravirsen microRNASantaris Phase II up to 12 Formerly Pharma mg/kg (SPC3649-LNA-antimiR ™- 122) CTS-1027 Anti- Conatus Phase II N/A inflammatoryOglufanide Immunomodulator Implicit Bioscience Phase II N/A disodiumAlinia Thiazolides Romark Phase II 500 mg (nitazoxanide) twice dailySCV-07 Broad Spectrum SciClone Phase II N/A Immune Stimulator MitoQInflammation/ Antipodean Phase II N/A (mitoquinone) Fibrosis InhibitorPharmaceuticals Debio 025 Cyclophilin Debio Phase II 600 to 1000Inhibitor mg/day PF-03491390 Pancaspase Pfizer Phase II 5 mg to 400(Formerly Inhibitor Pharmaceuticals mg daily IDN-6556) (given 1 to 3times a day)

According to the FDA-approved label dated Oct. 8, 2010, the recommendeddose of COPEGUS (ribavirin) tablets depends on body weight and the HCVgenotype to be treated, as shown in the following table.

HCV Genotype PEGASYS Dose* COPEGUS Dose Duration Genotypes 1, 4 180 μg <75 kg = 1000 mg 48 weeks ≧75 kg = 1200 mg 48 weeks Genotypes 2, 3 180μg 800 mg 24 weeks Genotypes 2 and 3 showed no increased response totreatment beyond 24 weeks. *See PEGASYS Package Insert for furtherdetails on PEGASYS dosing and administration

The COPEGUS label further discloses that the recommended duration oftreatment for patients previously untreated with ribavirin andinterferon is 24 to 48 weeks. The daily dose of COPEGUS is 800 mg to1200 mg administered orally in two divided doses. The dose should beindividualized to the patient depending on baseline diseasecharacteristics (e.g., genotype), response to therapy, and tolerabilityof the regimen.

An eighth embodiment is directed to a compound or a salt thereofrepresented by formula A,

wherein each one of Z¹, Z², and Z³ is hydrogen or a protecting group(PG).

In a first aspect of the eighth embodiment, PG is selected from among—C(O)alkyl, —C(O)aryl, —C(O)O(C₁₋₆alkyl), —C(O)O(C₁₋₆alkylene)aryl,—C(O)Oaryl, —CH₂O-alkyl, —CH₂O-aryl, —SO₂-alkyl, —SO₂-aryl, and asilicon-containing protecting group. One of ordinary skill willappreciate that Z¹ and Z² can be the same, while Z³ is different or thatZ¹ and Z² are a part of the same radical, such as in the instance of˜Si(C₁₋₆alkyl)₂OSi(C₁₋₆alkyl)₂˜, which would be derived from, forexample, a 1,3-dihalo-1,1,3,3-tetra(C₁₋₆alkyl)disiloxane.

In a second aspect of the eighth embodiment, PG is selected from among,benzoyl, acetyl, —C(O)OCH₂Ph, phenyl-substituted benzoyl,tetrahydropyranyl, trityl, DMT (4,4′-dimethoxytrityl), MMT(4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl)group, thiopixyl (9-phenylthioxanthen-9-yl),9-(p-methoxyphenyl)xanthine-9-yl (MOX), tert-butyldimethylsilyl,tert-butyldiphenylsilyl, and ˜Si(C₁₋₆alkyl)₂OSi(C₁₋₆alkyl)₂OH, such as,—Si(^(i)Pr)₂OSi(^(i)Pr)₂OH or ˜Si(^(i)Pr)₂OSi(^(i)Pr)₂˜.

In a third aspect of the eighth embodiment, each of Z¹, Z², and Z³ ishydrogen.

In a fourth aspect of the eighth embodiment, each of Z¹ and Z² ishydrogen and Z³ is benzoyl.

In a fifth aspect of the eighth embodiment, Z¹ and Z² are comprised of˜Si(^(i)Pr)₂OSi(^(i)Pr)₂- and Z³ is hydrogen or benzoyl.

A ninth embodiment is directed to a process for preparing a compoundrepresented by formula I-3-4′

wherein R¹ is as defined for compound I-3-4

or

a compound represented by formula I-3-5′,

wherein R^(1a), R^(1c), are as defined for compound I-3-5

said process comprising

reacting compound A′ with a nucleophile and optionally deprotecting toobtain compound B′

wherein the nucleophile is comprised of a radical selected from among—O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), and-cycloalkylamino, and wherein each one of Z¹, Z², and Z³ is hydrogen ora protecting group (PG) and reacting B′ with an appropriate reagent toobtain either I-3-4′ or I-3-5′.

Conditions for converting B′ to I-3-4′ are as described herein.Conditions for converting B′ to I-3-5′ are as described herein, e.g., asdescribed in the tenth embodiment.

In a first aspect of the ninth embodiment, the nucleophile is comprisedof a C₁₋₆alkoxide. The C₁₋₆alkoxide is obtained from methanol, ethanol,propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol,n-pentanol, isopentanol, neopentanol, t-pentanol, and hexanol.

In a second aspect of the ninth embodiment, the nucleophile is comprisedof a —OC₁₋₃alkaryl. The —OC₁₋₃alkaryl is obtained from the respectiveC₁₋₃alkaryl alcohol. For example, —OCH₂Ph is obtained frombenzylalcohol.

In a third aspect of the ninth embodiment, the nucleophile is comprisedof a C₁₋₆alkylthiolate. The C₁₋₆alkyl thiolate is obtained frommethylthiol, ethylthiol, propylthiol, i-propylthiol, n-butylthiol,i-butylthiol, s-butylthiol, t-butylthiol, n-pentylthiol, isopentylthiol,neopentylthiol, t-pentylthiol, and hexylthiol.

In a fourth aspect of the ninth embodiment, the nucleophile is comprisedof a —NH(C₁₋₆alkyl). The —NH(C₁₋₆alkyl) is obtained from methylamine,ethylamine, propylamine, i-propylamine, n-butylamine, i-butylamine,s-butylamine, t-butylamine, n-pentylamine, isopentylamine,neopentylamine, t-pentylamine, and hexylamine.

In a fifth aspect of the ninth embodiment, the nucleophile is comprisedof a -cycloalkylamino. The cycloalkylamino is derived from itsrespective cycloalkylamine.

In a sixth aspect of the ninth embodiment, the nucleophile is comprisedof a —C₃₋₆cycloalkylamino. The —C₃₋₆cycloalkylamino is obtained fromcyclopropylamine, 2-methyl-cyclopropylamine, cyclobutylamine,2-methyl-cyclobutylamine, cyclopentylamine, 2-methyl-cyclopentylamine,cyclohexylamine, 2-methyl-cyclohexylamine, etc.

In solution or in the solid-state the nucleophile, i.e., theC₁₋₆alkoxide (C₁₋₆alkylO⁻), the C₁₋₃alkaryloxide (⁻O(C₁₋₃alkaryl), theC₁₋₆alkylthiolate (C₁₋₆alkylS⁻), the C₁₋₆alkylamide (C₁₋₆alkylNH⁻), andthe cycloalkylamide (cycloalkylNH⁻) (or the C₃₋₆cycloalkylamide(⁻NHC₃₋₆cycloalkyl)), is associated with a cationic species, M. M isgenerally an alkali metal cation, such as Li⁺, Na⁺, K⁺, etc. or atetraalkyammonium, such as tetra-n-butyl-ammonium (^(n)Bu₄N⁺). However,M can be other cationic species so long as the association with thenucleophile permits reaction with A.

In each of the first six aspects of the ninth embodiment, thenucleophile can be pre-formed or prepared in situ. A pre-formednucleophile can be obtained commercially or prepared by procedures knownto one of ordinary skill. The so-prepared pre-formed nucleophile canoptionally be isolated as a solid or used directly in the reaction ofthe ninth embodiment. A nucleophile prepared in situ may occur in thepresence or absence of compound A. In the instance of a pre-formednucleophile or a nucleophile prepared in situ, the solvent used dependson the conditions of the reaction. In certain aspects a suitable solventis a polar aprotic solvent. Examples of polar aprotic solvents include,but are not limited to, DMSO, HMPA, DMF, THF, 2-methyl-THF, dioxane,cyclopentylmethylether, t-butyl-methylether, etc. In other aspects thenucleophile is obtained directly from the solvent. For example, thesolvent for the solvent for the first aspect of the ninth embodimentcould be an C₁₋₆alcohol (e.g., methanol, ethanol, etc.), in which theC₁₋₆alkoxide can be obtained according to conventional procedures.Solvents for the second and third aspects of the ninth embodimentinclude polar aprotic solvent, as well as an alcoholic solvent. Thesolvent for the fourth aspect of the ninth embodiment could be aC₁₋₆alkylamine (e.g., methylamine, ethylamine, etc.), in which theC₁₋₆alkylamide is obtained by adding a base having sufficient basicityto obtain the desired nucleophile. Likewise, the solvent for the fifthand sixth aspects of the ninth embodiment could be a cycloalkylamine ora C₃₋₆cycloalkylamine (e.g., cyclopropylamine, cyclobutylamine, etc.),in which the cycloalkylamide or the C₃₋₆cycloalkylamide is obtained byadding a base having sufficient basicity to obtain the desirednucleophile. The optional deprotection step is done by conventionalmeans.

A seventh aspect of the ninth embodiment is directed to a process forpreparing a compound represented by formula I-3-5′, which comprisesreacting compound A′ with a nucleophile to obtain compound B′, whereinthe nucleophile is comprised of a radical selected from among a—O(C₁₋₆alkyl), a —OC₁₋₃alkaryl, a —NH(C₁₋₆alkyl), and aC₃₋₆cycloalkylamino, and wherein for compound I-3-5′, R^(1a) and R^(1c)are as defined, and R¹⁶ is a —O(C₁₋₆alkyl). a —OC₁₋₃alkaryl, a—NH(C₁₋₆alkyl), and a C₃₋₆cycloalkylamino.

An eighth aspect of the ninth embodiment is directed to a process forpreparing a compound represented by formula I-3-5′, which comprisesreacting compound A′ with a nucleophile to obtain compound B′, whereinthe nucleophile is comprised of a radical selected from among a—O(C₁₋₆alkyl) and a —OC₁₋₃alkaryl, and wherein for compound I-3-5′,R^(1a) are R^(1c) are as defined, and R¹⁶ is a —O(C₁₋₆alkyl) or a—OC₁₋₃alkaryl.

A ninth aspect of the ninth embodiment is directed to a process forpreparing a compound represented by formula I-3-5′, which comprisesreacting compound A′ with a nucleophile to obtain compound B′, whereinthe nucleophile is comprised of a —O(C₁₋₆alkyl), and wherein forcompound I-3-5′, R^(1a) and R^(1c) are as defined, and R¹⁶ is a—O(C₁₋₆alkyl).

A tenth aspect of the ninth embodiment is directed to a process forpreparing a compound represented by formula I-3-5′, which comprisesreacting compound A′ with a nucleophile to obtain compound B′, whereinthe nucleophile is comprised of a —OC₁₋₃alkaryl, and wherein forcompound I-3-5′, R^(1a) and R^(1c) are as defined, and R¹⁶ is a—OC₁₋₃alkaryl.

In an eleventh aspect of the ninth embodiment, PG is selected from among—C(O)alkyl, —C(O)aryl, —C(O)O(C₁₋₆alkyl), —C(O)O(C₁₋₆alkylene)aryl,—C(O)Oaryl, —CH₂O-alkyl, —CH₂O-aryl, —SO₂-alkyl, —SO₂-aryl, and asilicon-containing protecting group. One of ordinary skill willappreciate that Z¹ and Z² can be the same, while Z³ is different or thatZ¹ and Z² are a part of the same radical, such as in the instance of˜Si(C₁₋₆alkyl)₂OSi(C₁₋₆alkyl)₂˜, which would be derived from, forexample, a 1,3-dihalo-1,1,3,3-tetra(C₁₋₆alkyl)disiloxane.

In a twelfth aspect of the ninth embodiment, PG is selected from among,benzoyl, acetyl, —C(O)OCH₂Ph, phenyl-substituted benzoyl,tetrahydropyranyl, trityl, DMT (4,4′-dimethoxytrityl), MMT(4-monomethoxytrityl), trimethoxytrityl, pixyl (9-phenylxanthen-9-yl)group, thiopixyl (9-phenylthioxanthen-9-yl),9-(p-methoxyphenyl)xanthine-9-yl (MOX), tert-butyldimethylsilyl,tert-butyldiphenylsilyl, and —Si(C₁₋₆alkyl)₂OSi(C₁₋₆alkyl)₂OH, such as,—Si(^(i)Pr)₂OSi(^(i)Pr)₂OH or ˜Si(^(i)Pr)₂OSi(Pr)₂˜.

In a thirteenth aspect of the ninth embodiment, each of Z¹, Z², and Z³is hydrogen.

In a fourteenth aspect of the ninth embodiment, each of Z¹ and Z² ishydrogen and Z³ is benzoyl.

In a fifteenth aspect of the ninth embodiment, Z¹ and Z² are comprisedof ˜Si(^(i)Pr)₂OSi(^(i)Pr)₂˜ and Z³ is hydrogen or benzoyl.

A tenth embodiment is directed to a process for preparing a compoundrepresented by formula I-3-5″,

wherein

R^(1a) is phenyl or naphthyl;

R^(1c) is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or C₁₋₃alkaryl; and

R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or-cycloalkylamino;

said process comprising:

reacting compound A″ with a nucleophile and optionally deprotecting toobtain compound B″,

wherein

R^(17′) is —NHZ³, wherein each one of Z¹, Z², and Z³ is hydrogen or aprotecting group (PG);

the nucleophile is comprised of a radical selected from among,—O(C₁₋₆alkyl), —OC₁₋₃alkaryl, —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), and-cycloalkylamino;

and

reacting B″ with a phosphoramidate represented by formula C to obtainI-3-5″

wherein the phosphoramidate is comprised of a mixture of the S_(P)- andR_(P)-diastereomers.

The optional deprotection step is done by conventional means.

In a first aspect of the tenth embodiment, R¹⁶ is —O(C₁₋₆alkyl),—OC₁₋₃alkaryl, —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or —NHC₃₋₆cycloalkyl.

In a second aspect of the tenth embodiment, R¹⁶ is —O(C₁₋₆alkyl).

In a third aspect of the tenth embodiment, R¹⁶ is —OC₁₋₃alkaryl.

In a fourth aspect of the tenth embodiment, R¹⁶ is —S(C₁₋₆alkyl).

In a fifth aspect of the tenth embodiment, R¹⁶ is —NH(C₁₋₆alkyl).

In a sixth aspect of the tenth embodiment, R¹⁶ is —NHC₃₋₆cycloalkyl.

In a seventh aspect of the tenth embodiment, the mole ratio of theS_(P)-diastereomer to the R_(P)-diastereomer ranges from about 2 toabout 99.99 and all values in between, including 2, 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99,99.9, and 99.99.

In an eighth aspect of the tenth embodiment, the mole ratio of theR_(P)-diastereomer to the S_(P)-diastereomer ranges from about 2 toabout 99.99 and all values in between, including 2, 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99,99.9, and 99.99.

In a ninth aspect of the tenth embodiment, the meanings of theprotecting group for A″ is as described for A in the eighth embodiment.

An eleventh embodiment is directed to a process for preparing a compoundrepresented by formula I-3-5′″

wherein R^(1a) is phenyl or naphthyl; R^(1c) is hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, or C₁₋₃alkaryl; R¹⁶ is —O(C₁₋₆alkyl), —OC₁₋₃alkaryl,—S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or -cycloalkylamino; and R¹⁷ is —H or—NH₂

said process comprising reacting a compound represented by formula B′″with a phosphoramidate represented by formula C to obtain I-3-5′″

wherein the phosphoramidate is comprised of a mixture of the S_(P)- andR_(P)-diastereomers.

In a first aspect of the eleventh embodiment, R¹⁶ is —O(C₁₋₆alkyl),—OC₁₋₃alkaryl, —S(C₁₋₆alkyl), —NH(C₁₋₆alkyl), or —NHC₃₋₆cycloalkyl andR¹⁷ is H or NH₂.

In a second aspect of the eleventh embodiment, the mole ratio of theS_(P)-diastereomer to the R_(P)-diastereomer ranges from about 2 toabout 99.99 and all values in between, including 2, 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99,99.9, and 99.99.

In a third aspect of the eleventh embodiment, the mole ratio of theR_(P)-diastereomer to the S_(P)-diastereomer ranges from about 2 toabout 99.99 and all values in between, including 2, 5, 10, 15, 20, 25,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99,99.9, and 99.99.

Preparation

Schemes 1-2 provide general procedures for preparing 2′-spiro-ara and2′-spiro-ribo-nucleosides.

The disclosed reagents are meant to be exemplary only and should not bemeant to narrow the scope of the embodiments disclosed below.

A seventh embodiment is directed to a process for preparing a compoundor its stereoisomer or its salt or its metabolite or its deuteriderepresented by formula I, by any of the processes disclosed herein.

A first aspect of the seventh embodiment is directed to a process forpreparing a compound or its stereoisomer or its salt or its metaboliteor its deuteride thereof wherein

is

said process comprising any one of the following reaction steps a′-h′PG

wherein B is defined above, PG is a protecting group, and LG is aleaving group.

A second aspect of the seventh embodiment is directed to a process forpreparing a compound or its stereoisomer or its salt or its metabolitethereof represented by formula I, wherein

is

said process comprising any one of the following reaction steps a′-h′

wherein B is as defined above, PG and PG′ are independent of one anotherleaving groups, and LG is a leaving group.

Scheme 3-6 provide general procedures for preparing additional compoundsof formula I. In these schemes, Pg, represents a protecting group, whichis defined herein. R is a substituent that provides for or is defined bythe substituent “Y” as defined herein. As described above, examples ofprotecting groups are defined herein and disclosed in Protective Groupsin Organic Synthesis, 3^(nd) ed. T. W. Greene and P. G. M. Wuts, JohnWiley & Sons, New York, N.Y., 1999. One of ordinary skill willappreciate the conditions available to protect and deprotect a givensynthetic intermediate. Additionally, it is contemplated that one ofordinary skill would employ known procedures for the deoxygenation stepsdisclosed below.

See, e.g., Kim C. M. F. Tjen, et al Chem. Commun., 2000, 699-700.

One of ordinary skill will appreciate that other methods of preparing acompound of formula I are possible.

Procedures for introducing substituents at the 1′ or 4′ positions aredisclosed in WO 2009/132135, as well as US 2009/0318380.

Procedures for preparing nucleosides and nucleotides of the “B” ofCompound I-2 are disclosed in U.S. Pat. Nos. 3,798,209, 4,138,547,4,458,016, 7,285,659, and 7,285,660.

Procedures for preparing nucleosides and nucleotides containing the “B”of Compound I-3-1 are disclosed in any one of WO 2010/075517, WO2010/075549, and WO 2010/075554.

Procedures for preparing nucleosides and nucleotides containing the “B6”of Compound I-3-7 (or I-3-9) are disclosed in any one of WO 2010/002877and WO 2009/132135.

Procedures for preparing nucleosides and nucleotides containing the “B7”of Compound I-3-7 (or I-3-10) are disclosed in any one of WO2010/036407, WO 2009/132135, and WO 2009/132123.

Procedures for preparing nucleosides and nucleotides containing the “B8”of Compound I-3-7 (or I-3-11) are disclosed in WO 2009/132123.

Procedures for preparing nucleosides and nucleotides containing the “B9”of Compound I-3-7 (or I-3-12) are disclosed in WO 2010/036407.

Procedures for preparing nucleosides and nucleotides containing the“B10” of Compound I-3-7 (or I-3-13) are disclosed in WO 2010/093608.

Procedures for preparing deuterides are known to one of ordinary skilland reference can be made to US 2010/0279973 and procedures disclosedtherein.

Procedures for preparing compound I-3-5″′ are disclosed herein.Additional procedures for preparing and isolating compound C aredisclosed in U.S. Ser. No. 13/076,552 (US 2011/0251152), filed on Mar.31, 2011 and U.S. Ser. No. 13/076,842 (US 2011/0245484), filed on Mar.31, 2011. To the extent necessary, the subject matter of U.S. Ser. No.13/076,552 and U.S. Ser. No. 13/076,842 is hereby incorporated byreference.

EXAMPLES

Not to be limited by way of example, the following examples serve tofacilitate a better understanding of the disclosure.

In the examples that follow, certain abbreviations have been used. Thefollowing table provides a selected number of abbreviations. It isbelieved that one of ordinary skill would know or be able to readilydeduce the meaning of any abbreviations not specifically identifiedhere.

Abbreviation Meaning TMSCl Trimethylsilylchloride TIPSCl1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane EtOAc Ethtyl Acetate Pyrpyridine Ac2O Acetic Anhydride THF Tetrahydrofuran DCM (≡CH₂Cl₂)Dichloromethane MsCl Mesylchloride HMDS Hexamethyldisiloxane MeCNAcetonitrile NMO N-Methylmorpholine-N-oxide p-TsOH para-toluene-sulfonicacid MOPS 3-(N-morpholino)propanesulfonic acid HCHO formaldehyde NaHMDSSodium bis(trimethylsilyl)amide NMI N-methylimidazole DTP1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

I. Preparation of 2′-Spiro-ara-uracil and 2′-Spiro-ribo-uracil Analogs

A. Preparation 2′-spiro-ara-uridines

The following scheme describes a possible synthetic route for thepreparation of 2′-spiro-ara-uracil analogs, 32 and 36. A syntheticintermediate common to compounds 32 and 36 is compound 28, which isobtained by protecting uridine 25 with1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPSCl) followed byoxidation of the 2′-carbon to form compound 27. Compound 28 is preparedby reacting compound 27 with an appropriate allyl-containing reagent.

Example 1 Preparation of1-((6aR,8R,9S,9aR)-9-allyl-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione,28 Step 1. Preparation of Compound 26

To a solution of compound 25 (20.0 g, 82.58 mmol) in anhydrous pyridine(150 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane(TIPSCl, 27.35 g, 86.71 mmol) at room temperature. The mixture wasstirred at room temperature for 20 h. The solvent was evaporated underreduced pressure and the residue was dissolved in EtOAc (200 mL). Theorganic solution was washed with H₂O and the solvent was evaporated togive a crude product 26 which was used for next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ=10.11 (s, 1H), 7.78 (d, J=8.4Hz, 1H), 5.73 (s, 1H), 5.68 (d, J=8.0 Hz, 1H), 4.07-4.38 (m, 4H),3.96-4.00 (m, 2H), 0.91-1.21 (m, 28H).

2. Preparation of Compound 27

To a stirred solution of CrO₃ (13.0 g, 130.0 mmol), anhydrous pyridine(22 mL) and Ac₂O (13 mL) was added a solution of compound 26 (20.0 g,41.28 mmol) in CH₂Cl₂ (50 mL). The mixture was stirred 60 min. Thesolution was filtered through to a short silica gel column. The solventwas evaporated and the residue was purified by silica gel columnchromatography (hexane:EtOAc=2:1) to give the compound 27 (9.0 g, 45%).¹H NMR (400 MHz, CDCl₃): δ=8.63 (s, 1H), 7.15 (d, J=8.0 Hz, 1H),5.72-5.74 (m, 1H), 5.05 (d, J=8.8 Hz, 1H), 4.99 (s, 1H), 4.09-4.17 (m,2H), 3.86-3.91 (m, 1H), 1.00-1.21 (m, 28H).

Step 3. Preparation of Compound 28

To a solution of compound 27 (5.0 g, 10.32 mmol) in THF (200 mL) wasadded a solution of allylmagnesium bromide (20.63 mL, 20.63 mmol) at−78° C. and the mixture was stirred at the same temperature for 2 h.Then the temperature was raised to −10° C. and the reaction was quenchedwith H₂O. The mixture was extracted with CH₂Cl₂ and the organic solutionwas dried with Na₂SO₄ and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(Hexanes:EtOAc=3:1) to give the compound 28 (4.0 g, 74%). ¹H NMR (400MHz, CDC₃): δ=8.82 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 6.04-56.14 (m. 1H),5.89 (s, 1H), 5.68 (d, J=8.0 Hz, 1H), 5.28-5.37 (m, 2H), 4.24 (d, J=9.2Hz, 1H), 4.15 (d, J=9.2 Hz, 1H), 3.97-4.01 (m, 1H), 3.78-3.80 (m, 1H),2.69-2.75 (m, 1H), 2.48-2.53 (m, 1H), 2.44 (s, 1H), 1.04-1.09 (m, 28H).

Example 2 Preparation of 1-((5S,6R,8R,9R)-9-hydroxy-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-6-yl)pyrimidine-2,4(1H,3H)-dione,32 (2′-spiro-THF-ara-uracil)

Step 1. Preparation of Compound 29

To a solution of compound 28 (2.0 g, 3.80 mmol) in THF (200 mL) wasadded BH₃ (0.57 mL, 5.7 mmol) at room temperature and the mixture wasstirred at room temperature for 3 hr. The reaction mixture was cooled to0° C. and 2 M aqueous NaOH (3.8 mL, 7.6 mmol) and 30% aqueous H₂O₂ (1.72mL, 15.21 mmol) was added slowly. The mixture was allowed to warm toroom temperature, stirred for 2 h and then poured into a mixture ofdiethyl ether (150 mL) and H₂O (150 mL). The aqueous phase was extractedwith diethyl ether (50 mL) and the combined organic solution was washedwith saturated aqueous NaHCO₃ (2×40 mL), and H₂O (2×40 mL),successively. The solution was dried (MgSO₄), filtered and evaporated todryness under reduced pressure. The residue was purified by silica gelcolumn chromatography (hexanes:EtOAc=1:1) to give the compound 29. (1.1g, 53%). ¹H NMR (400 MHz, CDCl₃): δ=10.39 (s, 1H), 8.00 (d, J=8.0 Hz,1H), 5.86 (s, 1H), 5.70 (d, J=8.0 Hz, 1H), 4.14-4.17 (m, 2H), 3.96-3.99(m, 2H), 3.70-3.73 (m, 1H), 3.47-3.52 (m, 1H), 2.02-2.17 (m, 2H),1.97-2.00 (m, 1H), 1.89-1.90 (m, 1H), 0.99-1.11 (m, 28H).

Step 2. Preparation of Compound 30

A solution of MsCl (0.28 g, 2.42 mmol) in anhydrous CH₂Cl₂ (1.0 mL) wasadded to a solution of nucleoside 29 (1.1 g, 2.02 mmol) in anhydrouspyridine (2.0 mL) drop-wise at room temperature. After stirring for 12 hat room temperature, methanol (0.1 mL) was added and the resultingmixture was evaporated to dryness under reduced pressure. The residuewas co-evaporated with anhydrous toluene (2×5 mL) and then dissolved inCH₂Cl₂ (50 mL). The solution was washed with saturated aqueous NaHCO₃(2×25 mL). The combined aqueous phase was extracted with CH₂Cl₂ (50 mL).The combined organic solution was dried (Na₂SO₄), filtered andevaporated to dryness under reduced pressure. The residue was purifiedby silica gel column chromatography (hexanes:EtOAc=2:1) to give compound30 (0.94 g, 74.6%).

3. Preparation of Compound 31

To a stirred suspension of NaH (108.8 mg, 4.53 mmol) in anhydrous THF(20 mL) was added a solution of compound 30 (0.94 g, 1.51 mmol) in THFdrop-wise at 0° C. and the mixture was stirred for 2 h at roomtemperature. Ice-cold H₂O (10 mL) was slowly added followed by additionof CH₂Cl₂ (20 mL). The organic phase was washed with saturated aqueousNaHCO₃ (2×20 mL) and dried (Na₂SO₄). Solvent was evaporated to drynessunder reduced pressure and the residue was purified by silica gel columnchromatography (Hexanes:EtOAc=2:1) to provide compound 31 (0.43 g,54.02%).

Step 4. Preparation of Compound 32

To a solution of compound 31 (150 mg, 0.285 mmol) in anhydrous THF (10mL) was added Et₃N.3HF (0.3 mL) and the mixture was stirred at roomtemperature for 2 h. The mixture was then evaporated to dryness underreduced pressure and the residue was purified by silica gel columnchromatography (0-15% MeOH in CH₂Cl₂) to give compound 32 (51.37 mg,63.5%). ¹H NMR (400 MHz, DMSO-d6): δ=11.32 (s, 1H), 7.80 (d, J=8.0 Hz,1H), 5.83 (s, 1H), 5.63 (d, J=4.2 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H),5.03-5.05 (m, 1H), 3.83-3.86 (m, 1H), 3.64-3.70 (m, 3H), 3.47-3.60 (m,2H), 2.27-2.29 (m, 1H), 1.74-1.81 (m, 3H). HRMS (TOF-ESI): Calc. ForC₁₂H₁₇N₂O₆, 285.1087. found 285.1070.

Example 3 Preparation of1-((4S,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)pyrimidine-2,4(1H,3H)-dione,36 (2′-spiro-oxetane-ara-uracil)

Step 1. Preparation of Compound 33

To a solution of compound 28 (4.8 g, 9.12 mmol) in DCM (200 mL) wasbubbled with O₃ and the solution was stirred at −78° C. for 3 h. To thesolution were added Me₂S (1 mL) and NaBH₄ (1.73 g, 45.60 mmol) at roomtemperature and the mixture was stirred overnight. The resultingsolution was washed with H₂O and the solvent was evaporated. The residuewas purified by silica gel column chromatography (hexanes:EtOAc=1:1) togive compound 33 (1.2 g, 25.7%). ¹H NMR (400 MHz, CDCl₃): δ 11.16 (s,1H), 7.92 (d, J=8.0 Hz, 1H), 6.01 (s, 1H), 5.69-5.72 (m, 1H), 5.64 (s,1H), 4.58-4.63 (m, 2H), 3.94-4.17 (m, 4H), 3.65-3.68 (m, 1H), 2.49-2.53(m, 1H), 1.58-1.61 (m, 1H), 1.01-1.11 (m, 28H).

Step 2. Preparation of Compound 34

A solution of MsCl (0.31 g, 2.72 mmol) in anhydrous CH₂Cl₂ (10 mL) wasadded to a solution of nucleoside 33 (1.2 g, 2.26 mmol) in anhydrouspyridine (2.0 mL) drop-wise at room temperature and the solution wasstirred at room temperature for 12 h. Methanol (5.0 mL) was added andthe resulting mixture was evaporated to dryness under reduced pressure.The residue was co-evaporated with anhydrous toluene (2×5 mL) andpurified by silica gel column chromatography (hexanes:EtOAc=2:1) toprovide compound 34 (1.0 g, 73.0%).

Step 3. Preparation of Compound 35

To a stirred suspension of NaH (59.2 mg, 2.467 mmol) in anhydrous THFwas added a solution of compound 10 (1.0 g, 1.65 mmol) in THF (3 mL)drop-wise at 0° C. and the mixture was stirred at room temperature for 2h at room temperature. Ice-cooled H₂O (10 mL) was slowly added to thesolution followed by addition of CH₂Cl₂ (20 mL). The organic phase waswashed with saturated aqueous NaHCO₃ (2×20 mL) and dried (Na₂SO₄).Solvent was evaporated to dryness under reduced pressure and the residuewas purified by silica gel column chromatography (hexanse:EtOAc=2:1) togive compound 35. (0.5 g, 59.25%).

Step 4. Preparation of Compound 36

To a solution of compound 35 (300 mg, 0.585 mmol) in anhydrous THF (10ml) was added Et₃N*3HF (0.15 mL) and the mixture was stirred at roomtemperature for 2 h. The mixture was then evaporated to dryness underreduced pressure and the residue was purified by silica gel columnchromatography (0-15% MeOH in CH₂Cl₂) to give compound 36 (61.26 mg,38.78%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.42 (s, 1H), 7.68 (d, J=8.0 Hz,1H), 6.08 (s, 1H), 5.87 (d, J=5.2 Hz, 1H), 5.60 (d, J=8.0 Hz, 1H),5.04-5.06 (m, 1H), 4.30-4.35 (m, 1H), 4.19-4.24 (m, 1H), 3.95-3.98 (m,1H), 3.50-3.61 (m, 3H), 3.01-3.08 (m, 1H), 2.39-2.45 (m, 1H). HRMS(TOF-ESI): Calc. for C₁₁H₁₅N₂O₆, 271.0925. found 271.0917.

B. Preparation of 2′-Spiro-Ribo-Uracil Analogs

The following scheme shows that 2′-spiro-ribo-uracil analogs can beprepared from a common synthetic intermediate, compound 40.

Example 4 Preparation of1-((6aR,8R,9R,9aR)-9-allyl-9-hydroxy-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione,40. Steps 1-2. Compound 39

Preparation of compound 39 was accomplished according to literaturemethod (Babu, B et al. Org Biomol. Chem. (2003) 1: 3514-3526). A mixtureof uracil (0.74 g, 6.59 mmol) and (NH₄)₂SO₄ (20 mg) in HMDS was refluxedfor 4 h and the clear solution was concentrated to dryness under reducedpressure. The residue was dissolved in MeCN (60 mL). To the solution wasadded a solution of compound 37 (2.0 g, 3.3 mmol) followed by SnCl₄ (1 Min CH₂Cl₂ (8.24 mmol, 8.24 mL) at room temperature and the solution washeated at 65° C. for 3 h. The solution was poured into ice-watercontaining excess NaHCO₃ and EtOAc (200 mL). Organic solution was washedwith brine and dried over Na₂SO₄. Solvent was evaporated and the residuewas purified by silica gel column chromatography (19-60% EtOAc inhexanes) to give compound 38 (1.50 g, 76%) as white foam.

A suspension of compound 38 (2.5 g, 4.19 mmol) in 7N methanolic ammonia(40 mL) was stirred at room temperature for 16 h and the solution wasevaporated to dryness. The residue was purified by silica gel columnchromatography (0-20% MeOH in CH₂Cl₂) to give compound 39 (1.0 g, 83%).¹H NMR (400 MHz, CD₃OD) δ: 7.96 (d, J=8.0 Hz, 1H), 6.01 (s, 1H), 5.89(m, 1H), 5.68 (d, J=8.0 Hz, 1H), 4.99 (m, 2H), 3.89 (m, 4H), 2.43 (m,1H), 2.23 (m, 1H).

Step 3. Preparation of Compound 40

To a solution of 39 (0.60 g, 2.11 mmol) in pyridine (10 mL) and CH₂Cl₂(20 mL) was added TIPSCl at 0° C. within 10 min. The solution wasstirred at room temperature for 24 h. Solvent was evaporated and theresidue was dissolved in EtOAc (100 mL). The solution was washed withbrine and dried over Na₂SO₄. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-5% MeOH in CH₂Cl₂) togive product 40 (1.00 g, 90%) as a syrup.

Example 5 Preparation of1-((5R,6R,8R,9R)-9-hydroxy-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-6-yl)pyrimidine-2,4(1H,3H)-dione,44 (2′-spiro-THF-ribo-uracil)

Step 1. Preparation of Compound 41

To a solution of 40 (1.0 g, 1.9 mmol) in THF (50 mL) was addedborane-dimethylsulfide (2.85 mmol, 0.22 g) and the solution was stirredat 0° C. for 3 h. To the cooled solution was added 2N NaOH (1.9 mL, 3.8mmol) and the mixture was stirred at room temperature for 2 h. EtOAc(100 mL) was added and the solution was washed with brine and dried overNa₂SO₄. Solvent was evaporated and the residue was purified by silicagel column chromatography (0-8% MeOH in CH₂Cl₂) to give product 41 (0.45g, 44%). ¹H NMR (400 MHz, CD₃OD) δ: 8.11 (s, 1H), 7.61 (D, J=8.0 Hz,1H), 6.05 (s, 1H), 5.71 (d, J=8.0 Hz, 1H), 4.07 (m, 4H), 3.60 (m, 3H),3.21 (s, 1H), 1.70 (m, 4H), 1.10 (m, 28H). LC-MS (ESI): 545 [M+H]⁺.

Steps 2-3. Preparation of Compound 43

To a solution of 41 (0.30 g, 0.55 mmol) in CH₂Cl₂ (10 mL) and pyridine(2 mL) was added a solution of MsCl (0.09 g, 0.83 mmol) in CH₂Cl₂ (1 mL)and the solution was stirred at room temperature for 3 h. Water (5 mL)was added and the mixture was washed with brine and dried over Na₂SO₄.Solvent was evaporated to dryness and the residue was purified by silicagel column chromatography (0-5% MeOH in CH₂Cl₂) to give intermediate 42(0.30 g, 87%). To THF (20 mL) was added NaH (60% in mineral oil, 0.05 g,2.01 mmol) and the mixture was stirred at room temperature for 10 min.To the mixture was added a solution of 42 (0.25 g, 0.40 mmol) in THF (10mL) and the mixture was stirred at room temperature for 1 h. Water (1mL) was added followed by addition of EtOAc (100 mL). The mixture waswashed with brine and dried over Na₂SO₄. Solvent was removed and theresidue was purified by silica gel column chromatography (0-50% EtOAc inhexanes) to give compound 43 (0.17 g, 80%). ¹H NMR (400 MHz, CD₃OD) δ:8.17 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 5.88 (s, 1H), 5.68 (dd, J=2.4, 8.4Hz, 1H), 4.26 (d, J=13.2 Hz, 1H), 4.01 (m, 5H), 1.90 (m, 4H), 1.05 (m,12H). LC-MS (ESI): 527 [M+H]⁺.

Step 4. Preparation of Compound 44

A mixture of 43 (0.05 g, 0.09 mmol) and NH₄F (100 mg) and catalytic TBAFin MeOH (10 mL) was refluxed for 5 h and the solvent was evaporated todryness. The residue was purified by silica gel column chromatography(0-10% MeOH in CH₂Cl₂) to give compound 44 (0.02 g, 93%) as white solid.¹H NMR (400 MHz, CD₃OD) δ: 8.09 (d, J=8.4 Hz, 1H), 5.91 (s, 1H), 5.68(d, J=8.4 Hz, 1H), 3.90 (m, 6H), 1.95 (m, 4H). LC-MS (ESI): 284 [M+H]⁺.

Example 6 Preparation of1-((4R,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)pyrimidine-2,4(1H,3H)-dione,48 (2′-spiro-oxetane-ribo-uracil)

Step 1. Preparation of Compound 45

To a solution of 40 (0.25 g, 0.47 mmol) in THF (5 mL), t-BuOH (50 mL)and water (0.8 mL) was added OsO₄ (0.5 mL, 2.5% in t-BuOH) followed byaddition of NMO (0.5 mL, 50% in water) and the mixture was stirred atroom temperature for 3 h. Solvent was evaporated and the residue wasco-evaporated with EtOH (20 mL) twice. The residue was dissolved in THF(8 mL) and water (2 mL). To the mixture was added NaIO₄ (0.29 g, 1.34mmol) and the mixture was stirred at room temperature for 2 h. To themixture was added MeOH (10 mL). To the mixture was added NaBH₄ (3 moleq) and the mixture was stirred at room temperature for 1 h. EtOAc (10mL) was added and the mixture was stirred at room temperature for 20min. Solid was filtered off. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-5% MeOH in CH₂Cl₂) togive compound 45 (0.16 g, 69%). ¹H NMR (400 MHz, CDC₃) δ: 9.35 (s, 1H),7.68 (d, J=8.0 Hz, 1H), 6.05 (s, 1H), 5.71 (d, J=8.0 Hz, 1H), 4.00 (m,8H), 1.80 (m, 2H), 1.00 (m, 12H). LC-MS (ESI): 531 [M+H]⁺.

Steps 2-3. Preparation of Compound 47

To a solution of 45 (0.25 g, 0.47 mmol) in CH₂Cl₂ (20 mL) and pyridine(2 mL) was added MsCl (0.10 g, 0.94 mmol) and the solution was stirredat room temperature for 3 h. Water (2 mL) was added and the solution wasevaporated to dryness. EtOAc (100 mL) was added and the organic solutionwas washed with water, brine and dried over Na₂SO₄. Solvent wasevaporated and the residue was purified by silica gel columnchromatography (0.80% EtOAc in hexanes) to give intermediate 46 whichwas dissolved in THF (10 mL). The solution was added into a mixture ofNaH (130 mg, 60% mineral oil) in THF (10 mL). The resulting mixture wasstirred at room temperature for 2 h and poured into EtOAc (100 mL). Theorganic solution was washed with water, brine and dried over Na₂SO₄.Solvent was evaporated and the residue was purified by silica gel columnchromatography (0-80% EtOAc in hexanes) to give compound 47 (0.054 g,64%). δ_(H) (CDC₃): 8.87 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 6.22 (s, 1H),5.68 (d, J=8.4 Hz, 1H), 4.60 (m, 2H), 4.21 (d, J=13.6 Hz. 1H), 4.00 (m,2H), 3.90 (m, 1H), 2.62 (m, 2H), 1.10 (m, 12H). LC-MS (ESI): 513 [M+H]⁺.

Step 4. Preparation of Compound 48

To a solution of 47 (0.07 g, 0.14 mmol) in MeOH (10 mL) was added NH₄F(100 mg) and the mixture was refluxed for 3 h. Solvent was evaporatedand the residue was purified by silica gel column chromatography (0-12%MeOH in CH₂Cl₂) to give compound 48. ¹H NMR (400 MHz, CD₃OD) δ: 7.93 (d,J=8.0 Hz, 1H), 6.17 (s, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.53 (m, 2H), 3.95(m, 2H), 3.72 (m, 2H), 2.60 (m, 2H). LC-MS (ESI): 270 [M+H]⁺.

II. Preparation of 2′-Spiro-Cytosine Analogs

Examples 7-10 describe procedures for converting a protected3′-5′-2′-spiro-uracil derivative to its corresponding cytidinederivative, as shown by the following equation.

Ex Starting Material

Product 12 43

49 13 31

50 14 35

51 15 47

52

Example 7 Preparation of4-amino-1-((5R,6R,8R,9R)-9-hydroxy-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-6-yl)pyrimidin-2(1H)-one,49. (2′-spiro-THF-ribo-cytidine)

To a solution of compound 43 (0.08 g, 0.14 mmol) in MeCN (10 mL) wasadded DMAP (0.02 g, 0.14 mmol) and Et₃N (0.07 g, 0.71 mmol) followed byaddition of TsCl (0.08 g, 0.43 mmol) and the solution was stirred atroom temperature for 1 h. To the solution was added NH₄OH (30%, 2 mL)and the mixture was stirred at room temperature for 1 h. Solvent wasevaporated to dryness and the residue was co-evaporated with toluenetwice to give crude cytosine analog which was dissolved in CH₂Cl₂ (10mL) and pyridine (1 mL). To the solution was added BzCl (0.1 mL, 0.86mmol) and the solution was stirred at room temperature for 2 h. Water (5mL) was added and the mixture was evaporated to dryness under reducedpressure. The residue was dissolved in EtOAc (100 mL) and the solutionwas washed with water, brine and dried over Na₂SO₄. Solvent wasevaporated and the residue was purified by silica gel columnchromatography (0-60% EtOAc in hexanes) to give N-benzoylcytosine analogwhich was dissolved in THF (10 mL). To the solution was added TBAF (0.12g, 0.48 mmol) and the solution was stirred at room temperature for 1 h.Solvent was evaporated and the residue was purified by silica gel column(0-8% MeOH in CH₂Cl₂) to give N-benzoyl nucleoside which was dissolvedin 7N NH₃ in MeOH (8 mL) and the solution was stirred at roomtemperature for 20 h. Solvent was evaporated and the residue waspurified by silica gel column (0-30% MeOH in CH₂Cl₂) to give product 49(0.09 g, 56% from 43). ¹H NMR (400 MHz, CD₃OD) δ: 8.09 (d, J=7.6 Hz,1H), 5.99 (s, 1H), 5.87 (d, J=7.6 Hz, 1H), 3.95 (m, 6H), 2.80 (m, 4H).LC-MS (ESI): 284 [M+H]⁺.

Example 8 Preparation of4-amino-1-((5S,6R,8R,9R)-9-hydroxy-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-6-yl)pyrimidin-2(1H)-one,50(2′-spiro-THF-cytidine)

Compound 50 is prepared from compound 31 using a procedure that isanalogous to that described in Example 7.

Data for 50: ¹H NMR (400 MHz, DMSO-d₆): δ=7.65 (d, J=7.2 Hz, 1H),7.05-7.19 (m, 2H), 5.98 (s, 1H), 5.68 (d, J=7.2 Hz, 1H), 5.57 (d, J=5.6Hz, 1H), 4.86-4.92 (m, 1H), 3.74-3.77 (m, 1H), 3.54-3.70 (m, 4H),3.35-3.38 (m, 1H), 2.17-2.24 (m, 1H), 1.66-1.85 (m, 3H). LC-MS(ESI): m/z283.9 [M+1]⁺. HRMS(TOF-ESI): Calc. For C₁₂H₁₈N₃O₅, 284.1241. found285.1235.

Example 9 Preparation of4-amino-1-((4S,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)pyrimidin-2(1H)-one,51 (2′-spiro-oxetane-ara-cytidine)

Compound 51 is prepared from compound 35 using a procedure that isanalogous to that described in Example 7.

Data for 51: ¹H NMR (400 MHz, DMSO-d₆): δ 7.55 (d, J=7.2 Hz, 1H),7.12-7.20 (m, 2H), 6.16 (s, 1H), 5.76 (d, J=5.2 Hz, 1H), 5.68 (d, J=8.0Hz, 1H), 4.91-4.94 (m, 1H), 4.24-4.29 (m, 1H), 4.06-4.11 (m, 1H),3.93-3.96 (m, 1H), 3.46-3.63 (m, 3H), 2.87-2.94 (m, 1H), 2.42-2.47 (m,1H). LC-MS(ESI): m/z 269.9 [M+1]⁺. HRMS (TOF-ESI): Calc. For C₁₁H₁₆N₃O₅,270.1084. found 270.1081.

Example 10 Preparation of4-amino-1-((4R,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)pyrimidin-2(1H)-one,52 (2′-spiro-oxetane-THF-cytidine)

Compound 52 is prepared from compound 47 using a procedure that isanalogous to that described in Example 7.

Data for 52: ¹H NMR (400 MHz, CD₃OD) δ: 8.097.98 (d, J=7.6 Hz, 1H), 6.26(s, 1H), 5.87 (d, J=7.6 Hz, 1H), 4.55 (m, 2H), 3.96 (m, 2H), 3.74 (m,2H), 2.54 (m, 2H). LC-MS (ESI): 270 [M+H]⁺.

III. Preparation of 2′-Spiro-Ara- and 2′-Spiro-Ribo Guanosine Analogs

A. Preparation of 2′-Spiro-Ara-Guanosine Analogs

Example 11 Preparation of(5S,6R,8R,9R)-6-(2-amino-6-methoxy-9H-purin-9-yl)-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-9-ol,62(2′-spiro-THF-ara-(2-amino-6-methoxy-purine) analogs)

Step 1. Preparation of Compound 54

To a solution of compound 53 (20.0 g, 66.29 mmol) in anhydrous methanol(400 mL) was added NaOMe (3.58 g, 66.29 mmol) at room temperature. Themixture was heated to reflux for 12 h. The solution was filtered and thefiltrate was evaporated to give a crude compound 54. (18.0 g, 91.14%).1H NMR (400 MHz, DMSO-d₆): δ=8.09 (s, 1H), 5.75 (d, J=5.6 Hz, 1H),4.41-4.44 (m, 1H), 4.02-4.09 (m, 1H), 3.96 (s, 3H), 3.86-3.89 (m, 1H),3.62 (dd, J=12.0 Hz, 4.0 Hz, 1H), 3.52 (dd, J=12.0 Hz, 4.0 Hz, 1H).

Step 2. Preparation of Compound 55

To a solution of compound 54 (18.0 g, 60.55 mmol) in anhydrous pyridine(200 mL) was added TIPSCl (22.9 g, 72.66 mmol) at room temperature. Themixture was stirred at room temperature for 20 h. Solvent was evaporatedunder reduced pressure and the residue was dissolved in EtOAc (200 mL).The solution was washed with H₂O, dried over Na₂SO₄ and evaporated togive a crude 55 which was used for next step without furtherpurification. (16.6 g, 50.8%). ¹H NMR (400 MHz, DMSO-d₆): δ=7.94 (s,1H), 6.47 (s, 1H), 5.76 (s, 1H), 5.63 (d, J=5.2 Hz, 1H), 4.38-4.41 (m,1H), 4.32-4.35 (m, 1H), 4.00-4.09 (m, 2H), 3.98 (s, 3H), 3.91-3.97 (m,1H), 0.94-1.04 (m, 28H).

Step 3. Preparation of Compound 56

To a solution of compound 55 (16.6 g, 30.8 mmol) in anhydrous CH₂Cl₂(200 mL) was added Et₃N (6.45 mL, 46.2 mmol) and TMSCl (4.99 g, 46.2mmol) at 0° C. The mixture was stirred room temperature for 10 h and thesolution was washed with H₂O, dried over Na₂SO₄ and the solvent wasevaporated. The residue was purified by silica gel column chromatography(hexanes:EtOAc=5:1) to give intermediate (16.5 g, 87.53%) which wasdissolved in pyridine (150 mL). To the solution was added solution ofCH₃COCl (1.92 ml, 26.96 mmol) in CH₂Cl₂ (5 mL) at 0° C. and the solutionwas stirred overnight at room temperature. The solvent was evaporatedand the residue was dissolved in CH₂Cl₂ (200 mL). The organic solutionwas washed with H₂O, dried with Na₂SO₄ and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexanes:EtOAc=5:1) to give the compound 56 (11.0 g, 62.5%).

Step 4. Preparation of Compound 57

To a solution of compound 56 (11.0 g, 17.65 mmol) in methanol (100 mL)was added p-TsOH (1.1 g, 6.39 mmol) and the resulting solution wasstirred overnight at room temperature. Solvent was evaporated and theresidue was dissolved in EtOAc (200 mL). The solution was washed withH₂O and dried with Na₂SO₄. Solvent was evaporated under reduced pressureand the residue was purified by silica gel column chromatography(hexanse:EtOAc=5:1) to give compound 57 (8.0 g, 77.9%). ¹H NMR (400 MHz,DMSO-d₆): δ=10.39 (s, 1H), 8.28 (s, 1H), 5.87 (s, 1H), 5.61 (d, J=4.4Hz, 1H), 4.49-4.51 (m, 2H), 4.07-4.11 (m, 1H), 4.03 (s, 3H), 4.00-4.02(m, 1H), 3.91-3.94 (m, 1H), 2.22 (s, 3H), 0.94-1.04 (m, 28H).

Step 5. Preparation of Compound 58

To a stirred solution of CrO₃ (2.58 g, 25.8 mmol), anhydrous pyridine(4.18 mL, 51.6 mmol) and Ac₂O (2.47 mL, 25.8 mmol) was added a solutionof compound 57 (5.0 g, 8.61 mmol) in CH₂Cl₂ (100 mL). The mixture wasstirred 60 min and filtered through a short silica gel column. Thefiltrate was evaporated and the residue was purified by silica gelcolumn chromatography (hexanes:EtOAc=3:1) to give compound 58 (3.0 g,60.0%)

Step 6. Preparation of Compound 59

To a solution of compound 58 (3.0 g, 5.18 mmol) in THF (100 mL) wasadded solution of allylmagnesium bromide (10.36 mL, 10.36 mmol) at −78°C. and the mixture was stirred for 2 h at the same temperature. Then thetemperature was raised to −10° C. and the reaction was quenched withH₂O. The mixture was extracted with DCM. The organic solution was driedwith Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexanes:EtOAc=3:1) to givecompound 59 (2.0 g, 62.5%). ¹H NMR (400 MHz, DMSO-d₆): δ=10.36 (s, 1H),8.17 (s, 1H), 5.99 (s, 1H), 5.82-5.90 (m, 1H), 5.49 (s, 1H), 5.01-5.20(m, 2H), 4.46 (d, J=7.2 Hz, 1H), 4.07 (s, 3H), 3.97-4.06 (m, 3H),2.48-2.58 (m, 2H), 2.26 (s, 3H), 0.94-1.04 (m, 28H).

Step 7. Preparation of Compound 60

To a solution of 59 (1.20 g, 2.07 mmol) in THF (60 mL) was addedBH₃.SMe₂ (0.5 mL, excess) and the solution was stirred at 0° C. for 1 h.To the solution was added an additional BH₃.SMe₂ (0.5 mL, excess) andthe solution was stirred at 0° C. for 2 h. To the resulting solution wasadded 2N NaOH (2 mL) followed by the addition of H₂O₂ (30%, 2 mL) andthe mixture was stirred at room temperature for 1 h. To the mixture wasadded additional 2N NaOH (2 mL) followed by the addition of H₂O₂ (30%, 2mL) and the mixture was stirred at room temperature for 2 h. EtOAc (200mL) was added and the mixture was washed with brine and dried overNa₂SO₄. Solvent was evaporated and the residue was purified by silicagel column (0-80% EtOAc in hexanes) to give product 60 (0.28 g, 22.7%)as foam. ¹H NMR (400 MHz CDCl₃): 8.48 (s, 1H), 8.07 (s, 1H), 6.41 (br s,1H), 6.15 (s. 1H), 5.00 (br s, 1H), 4.48 (d, J=9.2 Hz, 1H), 4.21 (d,J=13.6 Hz, 1H), 4.13-4.03 (m, 2H), 4.00 (s, 3H), 3.81 (J=8.4 Hz, 1H),3.47 (m, 1H), 2.28-1.98 (m, 7H), 1.08 (m, 28H). LC-MS (ESI): 640 [M+H]⁺.

Step 8. Preparation of Compound 61

To a solution of compound 60 (0.28 g, 0.44 mmol) in CH₂Cl₂ (20 mL) andpyridine (1 mL) was added MsCl (0.3 mL, 3.88 mmol), and the solution wasstirred at room temperature for 3 h. Water (10 mL) was added and themixture was extracted with EtOAc (100 mL). The organic solution waswashed with brine and dried over Na₂SO₄. Solvent was removed and theresidue was used for the next reaction without purification.

To a solution of the mesylate obtained above in THF (30 mL) was addedNaH (60% in mineral oil, 0.3 g, 7.5 mmol) and the mixture was stirred atroom temperature for 2 h. Water (10 mL) was added slowly. The mixturewas extracted with EtOAc (100 mL). The organic solution was washed withbrine and dried over Na₂SO₄. Solvent was evaporated and the residue wasdissolved in MeOH (10 mL). To the solution was added NH₄F (0.20 g, 5.40mmol) and the mixture was heated at reflux for 5 h. Solvent wasevaporated and the residue was purified by silica gel column (0-10% MeOHin CH₂Cl₂) to give product 61. (0.20 g, 47.8%). ¹NMR (400 MHz CD₃OD):8.8.46 (s, 1H), 6.26 (s, 1H), 4.20 (m, 4H), 3.90 (m, 1H), 3.85 (m, 2H),3.71 (m, 1H), 3.34 (m, 1H), 2.41 (m, 1H), 2.34 (s, 3H), 1.86 (m, 3H).LC-MS (ESI): 380 [M+H]⁺.

Step 9. Preparation of Compound 62

To a solution of compound 61 (0.08 g, 0.21 mmol) in MeOH (5 mL) wasadded NaOMe (4.8 M, 0.4 mL) and the solution was stirred at roomtemperature for 24 h. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-15% MeOH in CH₂Cl₂) togive a solid which was recrystallized from MeOH in EtOAc to product 62as white solid (0.04 g, 56%). ¹NMR (400 MHz CD₃OD): 8.05 (s, 1H), 6.07(s, 1H), 4.08 (m, 1H), 4.91 (m, 1H), 3.83 (m, 2H), 3.75 (m, 1H), 3.35(m, 1H), 3.30 (s, 3H), 2.40 (m, 1H), 1.86 (m, 2H), 1.61 (m, 1H). LC-MS(ESI): 338 [M+H]⁺.

Example 12 Preparation of(4S,5R,7R,8R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol,66 (2′-spiro-oxtane-ara-(2-amino-6-methoxy-purine) analog)

Step 1. Preparation of Compound 64

To a solution of compound 63 (1.7 g, 2.74 mmol) in DCM (250 mL) wasbubbled with O₃ and the solution was stirred at −78° C. for 3 h. To thesolution were added Me₂S (1 mL) and NaBH₄ (0.104 g, 2.74 mmol) at roomtemperature. The mixture was stirred overnight and extracted withCH₂Cl₂. The organic solution was dried with Na₂SO₄. Solvent wasevaporated and the residue was purified by silica gel columnchromatography (hexanes:EtOAc=1:1) to give compound 64 (0.8 g, 47.06%).

Step 2. Preparation of Compound 65

A solution of MsCl (0.22 g, 1.92 mmol) in anhydrous CH₂Cl₂ (3 mL) wasadded to a solution of 64 (0.80 g, 1.28 mmol) in anhydrous pyridine (5.0ml) drop-wise at room temperature and the solution was stirred at roomtemperature for 12 h. Methanol (5.0 mL) was added and the resultingmixture was evaporated to dryness under reduced pressure. The residuewas co-evaporated with anhydrous toluene (2×5 mL) and purified by silicagel column chromatography (hexanes:EtOAc=3:1) to give the mesylate (0.50g, 55.6%). ¹H NMR (400 MHz, CDC₃): δ=8.15 (s, 1H), 8.09 (s, 1H), 5.95(s, 1H), 4.66-4.69 (m, 2H), 4.51 (d, J=7.6 Hz, 1H), 4.10 (s, 3H),4.05-4.11 (m, 2H), 3.81-3.87 (m, 1H), 2.97 (s, 3H), 2.50-2.58 (m, 1H),2.38 (s, 3H), 2.19-2.24 (m, 1H), 0.94-1.04 (m, 28H).

To a stirred suspension of NaH (113.8 mg, 2.84 mmol) in anhydrous THF(10 mL) was added a solution of the mesylate (0.50 g, 0.71 mmol) in THF(5 mL) drop-wise at 0° C. and the mixture was stirred at roomtemperature for 2 h. The reaction was quenched by addition of ice-coldH₂O (10 mL) slowly and the mixture was extracted with CH₂Cl₂. Theorganic phase was washed with saturated aqueous NaHCO₃ (2×20 mL), dried(Na₂SO₄), filtered and evaporated to dryness under reduced pressure togive 2′-oxetane-intermediate (0.4 g, 92.6%). ¹H NMR (400 MHz, CDCl₃):δ=8.48 (s, 1H), 8.19 (s, 1H), 6.29 (s, 1H), 4.86 (d, J=6.8 Hz, 1H),4.21-4.29 (m, 2H), 4.14 (s, 3H), 3.98-4.03 (m, 1H), 3.81-3.89 (m, 2H),3.25-3.34 (m, 1H), 2.53 (s, 3H), 2.45-2.52 (m, 1H), 0.94-1.04 (m, 28H).

To a stirred solution of 2′-oxetane-intermediate (400 mg, 0.658 mmol) inanhydrous methanol (50 mL) was added NaOMe (71.28 mg, 1.32 mmol) and thesolution was stirred at room temperature for 20 h. The solution wasevaporated to give compound 65 (0.3 g, 92.6%).

Step 3. Preparation of Compound 66

To a stirred solution of 65 (300 mg, 0.53 mmol) in anhydrous methanol(30 mL) was added NH₄F (39.28 mg, 1.06 mmol) at room temperature and thesolution was heated to refluxed for 10 h. The solution was evaporatedand the residue was purified by silica gel column chromatography(CH₂Cl₂:MeOH=20:1) to provide compound 66 (36.0 mg, 21.05%). ¹H NMR (400MHz, DMSO-d₆): δ=7.94 (s, 1H), 6.52 (s, 2H), 6.09 (s, 1H), 5.92 (d,J=5.2 Hz, 1H), 5.02 (t, J=5.2 Hz, 1H), 4.28-4.30 (m, 1H), 4.17-4.19 (m,1H), 3.97 (s, 3H), 3.94-3.97 (m, 1H), 3.69-3.73 (m, 1H), 3.53-3.59 (m,2H), 2.95-2.98 (m, 1H), 2.35-2.37 (m, 1H). HRMS (TOF-ESI): Calc. ForC₁₃H₁₇N₅O₅, 324.1308. found 324.1306.

B. Preparation of 2′-Spiro-Ribo-Guanosine Analogs

Example 13 Preparation of(5R,6R,8R,9R)-6-(2-amino-6-methoxy-9H-purin-9-yl)-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-9-ol,72 (2′-spiro-THF-ribo-(2-amino-6-methoxy-purine) analog)

Step 1. Preparation of Compound 67

To a precooled (0° C.) solution of compound 37 (4.00 g, 6.59 mmol) and6-chloroguanine (1.68 g, 9.89 mmol) in MeCN (80 mL) were added DBN (2.46g, 19.78 mmol) then TMSOTf (5.86 g, 26.38 mmol), and the solution washeated at 65° C. for 5 h then room temperature for 16 h. The solutionwas cooled to room temperature and poured into a mixture of EtOAc (300mL) and excess NaHCO₃ with ice. Organic solution was washed with NaHCO₃,brine and dried over Na₂SO₄. Solvent was evaporated and the residue waspurified by silica gel column chromatography (5-60% EtOAc in hexanes) togive compound 67 (3.2 g, 74%). ¹NMR (400 MHz CD₃OD): δ: 8.18-7.25 (m, 16Hz), 6.73 (s, 1H), 5.40 (m, 3H), 5.12 (m, 2H), 4.82 (m, 1H), 4.74 (m,3H), 3.04 (m, 1H), 2.52 (m, 1H). LC-MS (ESI): 654 [M+H]⁺.

Step 2. Preparation of Compound 68

To a mixture of compound 67 (3.20 g, 4.89 mmol) in MeOH (80 mL) wasadded 25% NaOMe in MeOH 1.86 g, 48.92 mmol) and the solution was stirredat room temperature for 24 h. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-15% MeOH in CH₂Cl₂) togive product 68 as white solid. ¹NMR (400 MHz CD₃OD): δ: 8.13 (s, 1H),5.97 (s, 1H), 5.67 (m, 1H), 4.77 (m, 1H), 4.56 (m, 1H), 4.45 (d, J=8.8Hz, 1H), 4.13-3.83 (m, 6H), 2.25 (m, 1H), 2.05 (m, 1H). LC-MS (ESI): 338[M+H]⁺.

Step 3. Preparation of Compound 69

To a solution of compound 68 (1.33 g, 3.94 mmol) in pyridine (20 mL) wasadded TIPSCl (1.37 g, 4.34 mmol) and the solution was stirred at roomtemperature for 16 h. Solvent was evaporated and the residuere-dissolved in EtOAc (400 mL) and the solution was washed with brineand dried over Na₂SO₄. Solvent was evaporated and the residue purifiedby silica gel column chromatography (0-5% MeOH in CH₂Cl₂) to giveintermediate (1.30 g, 57%). ¹NMR (400 MHz CD₃OD): δ: 7.757 (s, 1H), 5.93(s, 1H), 5.66 (m, 1H), 4.88 (m, 1H), 4.82 (s, 2H), 4.73 (d, J=7.6 Hz,1H), 4.64 (m, 1H), 4.20 (m, 1H), 4.08 (m, 7H), 2.20 (m, 2H), 1.07 (m,28H). LC-MS (ESI): 450 [M+H]⁺. To a solution of the intermediate inpyridine (10 mL) and CH₂Cl₂ (20 mL) was added benzoyl chloride (0.63 g,4.48 mmol) and the solution was stirred at room temperature for 5 h.Water (10 mL) was added and the solution was evaporated to give aresidue which was dissolved in EtOAc (200 mL). Organic solution waswashed with brine and dried over Na₂SO₄. Solvent was evaporated and theresidue was purified by silica gel column chromatography (0-5% MeOH inCH₂Cl₂) to give compound 69 (1.50 g, 98%) as foam. δ_(H) (CD₃OD): 8.46(s, 1H), 7.78 (m, 6H), 5.98 (s, 1H), 5.72 (m, 1H), 5.00 (d, J=8.0 Hz,1H), 4.83 (d, J=10.4 Hz, 1H), 4.50 (m, 1H), 4.35 (m, 1H), 4.10 (m, 5H),2.32 (m, 1H), 2.20 (m, 1H), 1.05 (m, 28H). LC-MS (ESI): 684 [M+H]⁺.

Step 4. Preparation of Compound 70

To a solution of compound 69 (0.20 g, 0.29 mmol) in THF (20 mL) wasadded BH₃.SMe₂ (0.15 g, 1.46 mmol) and the solution was stirred at 0° C.for 3 h. To the solution was added 2N NaOH (2N, 1 mL) then H₂O₂ (0.5 mL)at 0° C. The mixture was stirred at room temperature for 2 h. EtOAc (100mL) was added and the solution was washed with brine and dried overNa₂SO₄. Solvent was evaporated and the residue was purified by silicagel column chromatography (0-100% EtOAc in hexanes) to give compound 70(0.07 g, 33%). ¹NMR (400 MHz CD₃OD): δ: 8.60 (s, 1H), 8.31 (s, 1H), 7.65(m, 5H), 6.26 (s, 1H), 4.47 (d, J=8.8 Hz, 1H), 4.26 (m, 2H), 4.10 (m,4H), 3.50 (m, 2H), 1.83 (m, 1H), 1.61 (m, 2H), 1.27 (m, 1H), 1.10 (m,28H). LC-MS (ESI): 702 [M+H]⁺.

Step 5. Preparation of Compound 71

To a solution of compound 70 (0.05 g, 0.07 mmol) in CH₂Cl₂ (10 mL) andpyridine (0.5 mL) was added MsCl (0.1 mL g, excess) and the solution wasstirred at room temperature for 2 h. EtOAc (100 mL) was added to thereaction. The mixture was washed with brine and dried over Na₂SO₄.Solvent was evaporated and the residue was co-evaporated with toluenetwice to give mesylate. To a solution of the mesylate in THF (10 mL) wasadded NaH (60% in mineral oil, 0.06 g, 1.50 mmol) and the mixture wasstirred at room temperature for 2 h. EtOAc (100 mL) was added and theorganic solution was washed with brine and dried over Na₂SO₄. Solventwas evaporated and the residue was dissolved in MeOH (10 mL). To thesolution was added NH₄F (0.10 g, 2.75 mmol) and the mixture was refluxedat 60 OC for 4 h. Solvent was evaporated and the residue was purified bysilica gel column chromatography (0-10% MeOH in CH₂Cl₂) to give product71 (0.023 g, 74% from 70) as white solid. ¹NMR (400 MHz CD₃OD): δ: 8.63(s, 1H), 7.80 (m, 5H), 6.20 (s, 1H), 4.59 (m, 1H), 4.00 (m, 9H), 1.94(m, 3H), 1.36 (m, 1H). LC-MS (ESI): 440 [M+H]⁺.

Step 6. Preparation of Compound 72

To a solution of 71 (0.03 g, 0.07 mmol) in MeOH (5 mL) was added NaOMe(0.11 g, 2.00 mmol) and the solution was stirred at room temperature for2 days. Solvent was evaporated and the residue was purified by silicagel column chromatography (0-15% MeOH in CH₂Cl₂) to give nucleoside 72(0.02 g, 87%) as white solid. ¹NMR (400 MHz CD₃OD): δ: 8.24 (s, 1H),5.97 (s, 1H), 4.36 (d, J=9.6 Hz, 1H), 4.00 (m, 8H), 1.94 (m, 2H), 1.80(m, 1H), 1.34 (m, 1H). LC-MS (ESI): 338 [M+H]+.

The corresponding guanosine derivative of 72 is prepared in a manneranalogous to Example 15.

Example 14 Preparation of(4R,5R,7R,8R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol,76 (2′-spiro-oxetane-ribo-(2-amino-6-methoxy-purine) analog)

Step 1. Preparation of Compound 74

To a mixture of compound 73 (0.30 g. 0.44 mmol) in THF (6 mL), t-Butanol(6 mL) and water (1 mL) was added 0.25% OsO₄ in t-Butanol (0.5 mL)followed by addition of 50% NMO (0.2 mL, 0.85 mmol) and the mixture wasstirred at room temperature for 16 h. Solvent was evaporated and theresidue was co-evaporated with toluene twice to give diol as a mixtureof diastereomers which was dissolved in THF (10 mL). To the solution wasadded water (1 mL) followed by addition of NaIO₄ (excess) portion-wiseuntil starting material disappeared at room temperature for 3 h. EtOAc(100 mL) was added and the solution was washed with brine and dried overNa₂SO₄. Solvent was evaporated and the residue was dissolved in EtOAc(10 mL) and EtOH (10 mL). To the pre-cooled solution at 0° C. was addedNaBH₄ (50.16 mg, 1.32 mmol) and the mixture was stirred at 0° C. for 1h. EtOAc (100 mL) was added and the residue was purified by silica gelcolumn chromatography (0-10% MeOH in CH₂Cl₂) to give compound 74 (0.14g, 43% from 73). ¹NMR (400 MHz CDCl₃): δ: 8.57 (s, 1H), 8.48 (s, 1H),7.70 (m, 5H), 6.26 (s, 1H), 4.15 (m, 9H), 1.28 (m, 2H), 1.15 (m, 28H).LC-MS (ESI): 688 [M+H]⁺.

Step 2. Preparation of Compound 75

To a solution of compound 74 (0.33 g, 0.47 mmol) in CH₂Cl₂ (30 mL) andpyridine (3 mL) was added MsCl (0.11 g, 0.94 mmol) and the solution wasstirred at room temperature for 3 h. Water (10 mL) was added and themixture was extracted with EtOAc (100 mL). The solution was washed withbrine and dried over Na₂SO₄. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-100% EtOAc in hexanes)to give mesylate (0.30 g, 82%). δ_(H) (CDCl₃): 8.53 (s, 1H), 8.21 (s,1H), 7.65 (m, 5), 6.14 (s, 1H), 4.80 (s, 1H), 4.54 (m, 2H), 4.33 (m,1H), 4.16 (s, 3H), 4.10 (m, 3H), 2.95 (s, 3H), 2.05 (m, 2H), 1.05 (m,28H). LC-MS (ESI): 766 [M+H]. To a solution of mesylate (0.20 g, 0.26mmol) in THF (10 mL) was added NaH (60% mineral oil, 110 mg, 2.75 mmol)and the mixture was stirred at room temperature for 1 h. The mixture waspoured into EtOAc (100 mL) and the solution was washed with brine anddried over Na₂SO₄. Solvent was evaporated and the residue was purifiedby silica gel column chromatography (0-80% EtOAc in hexanes) to giveoxetane-intermediate (0.15 g, 57%). ¹NMR (400 MHz CDCl₃): δ: 8.47 (s,1H), 8.23 (s, 1H), 7.65 (m, 5H), 6.38 (s, 1H), 7.74 (m, 1H), 4.59 (m,1H), 4.46 (d, J=9.2 Hz, 1H), 4.26 (d, J=13.2 Hz, 1H), 4.15 (s, 3H), 4.00(m, 2H), 2.56 (m, 2H), 1.09 (m, 28H). LC-MS (ESI): 686 [M+H]+.

To the solution of the oxetane-intermediate in MeOH (10 mL) was addedNH₄F (1.3 mmol, 46.8 mg) and the mixture was heated at 60° C. for 5 h.Solvent was evaporated and the residue was purified by silica gel columnchromatography (0-10% MeOH in CH₂Cl₂) to give compound 75 (0.05 g, 43%from 74) as white solid. LC-MS (ESI): 428 [M+H]⁺.

Step 3. Preparation of compound 76

A solution of compound 75 (0.20 g, 0.45 mmol) in MeOH (10 mL) was addedNaOMe (4.8 M, 0.8 mL) and the solution was stirred at room temperaturefor 20 h. Solvent was evaporated and the residue was purified by silicagel column chromatography (0-15% MeOH in CH₂Cl₂) to give compound 76(0.10 g, 69%). ¹NMR (400 MHz CD₃OD): δ: 8.15 (s, 1H), 6.26 (s, 1H), 4.50(m, 3H), 4.05 (s, 3H), 3.96 (m, 1H), 3.80 (m, 2H), 2.57 (m, 1H), 2.27(m, 1H). LC-MS (ESI): 324 [M+H]⁺.

Example 15 Preparation of2-amino-9-((4R,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)-1H-purin-6(9H)-one,77 (2′-spiro-oxetane-ribo-guanosine)

To a solution of compound 76 (0.04 g, 0.12 mmol) in MOPS buffer (0.1 M,10 mL) was added adenosine deaminase (2.0 mg) and the solution was keptat 37° C. for 2 days. Solvent was evaporated and the residue waspurified by silica gel column chromatography (0-30% MeOH in CH₂Cl₂) togive a crude compound 77 which was recrystallized from MeOH to removecrystalline of phosphate salt from buffer. The residue was re-dissolvedin MeOH (50 mL) and formic acid (1 mL) was added. The solution wasevaporated and the residue was co-evaporated with toluene twice. Theresulting solid was purified by silica gel column chromatography (0-30%MeOH in CH₂Cl₂) to give product 77 as white solid (0.02 g, 65%). ¹NMR(400 MHz CD₃OD): δ: 8.04 (s, 1H), 6.21 (s, 1H), 4.54 (m, 2H), 4.36 (d,J=8.8 Hz, 1H), 4.94 (m, 1H), 3.78 (m, 2H), 2.60 (m, 1H), 2.33 (m, 1H).LC-MS (ESI): 310 [M+H]⁺.

IV. Preparation of 2′-Spiro-Ara- and 2′-Spiro-Ribo-Adenine Analogs

A. Preparation of 2′-Spiro-Ara-Adenine Analogs

Example 16 Preparation of(4S,5R,7R,8R)-5-(6-amino-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol,87

Compound 87 is prepared using an eight-step reaction sequence thatbegins with adenine (78).

Step 1: Preparation of Compound 79

Compound 78 (30.0 g, 112.26 mmol) was dried by co-evaporation withanhydrous pyridine three times and dissolved in dry pyridine (400 mL).To the solution was added TMSCl (60.98 g, 561.3 mmol) and the solutionwas stirred for 1 h at 0° C. To the resulting solution was added benzoylchloride (78.9 g, 561.3 mmol) dropwise and the mixture was stirred 3 hat room temperature. The mixture was cooled to 0° C. and H₂O (120 mL)was added, and the resulting mixture was stirred for 0.5 h. NH₃.H₂O(30%, 230 mL) was added and the mixture was stirred for 2 h. Solid wascollected by filtration and washed with H₂O and EtOAc to give crudeproduct 79. (38.0 g, 91.6%)

¹H NMR (400 MHz, DMSO-d₆) δ: 8.77 (s, 1H), 8.74 (s, 1H), 8.05 (d, J=7.2Hz, 2H), 7.62-7.66 (m, 1H), 7.53-757 (m, 2H), 6.05 (d, J=6.0 Hz, 1H),4.66 (t, J=5.8 Hz, 1H), 4.20 (t, J=4.8 Hz, 1H), 3.99 (dd, J=7.6 Hz, 3.6Hz, 1H), 3.69 (dd, J=8.0 Hz, 4.0 Hz, 1H), 3.58 (dd, J=8.0 Hz, 4.0 Hz,1H),

Step 2: Preparation of Compound 80

To a solution of compound 79 (38.0 g, 102.33 mmol) in anhydrous pyridine(200 mL) was added TIPSCl (38.7 g, 122.8 mmol) and the mixture wasstirred for 20 h at room temperature. Solvent was removed under reducepressure and the residue was dissolved in EtOAc (200 mL). The solutionwas washed with H₂O and the solvent was removed to give 80 which wasused for next step without further purification. (45.0 g, 71.62%)

Step 3: Preparation of Compound 81

To a stirred solution of CrO₃ (20.0 g, 32.58 mmol), anhydrous pyridine(15.8 mL, 195.48 mmol) and Ac₂O (9.5 mL, 97.74 mmol) was added asolution of compound 80 (20.0 g, 32.58 mmol) in CH₂Cl₂. (100 mL). Themixture was stirred at room temperature for 60 min. The solution waspassed through a short silica gel column. Solvent was removed and theresidue was purified by silica gel column chromatography(hexane:EtOAc=3:1) to give compound 81 (4.0 g, 21.2%)

Step 4: Preparation of Compound 82

To a solution of compound 81 (4.0 g, 6.9 mmol) in THF (100 mL) was addeda solution of allylmagnesium bromide (13.82 mL, 3.82 mmol) at −78° C.and the resulting mixture was stirred for 2 hours at the sametemperature. Then the temperature was increased to −10° C. and thereaction mixture was quenched with H₂O and extracted with DCM. Theorganic layer was dried with Na₂SO₄ and solvent was removed underreduced pressure. The residue was purificated by silica gel columnchromatography. (hexane:EtOAc=2:1) to give compound 82 (1.6 g, 35.5%).¹H NMR (400 MHz, DMSO-d₆) δ: 11.20 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H),8.04 (d, J=8.8 Hz, 2H), 7.53-7.65 (m, 3H), 6.17 (s, 1H), 5.82-5.95 (m,1H), 5.55 (s, 1H), 515-5.23 (m, 1H), 5.02-5.10 (m, 1H), 4.60 (d, J=7.2Hz, 1H), 3.85-4.10 (m, 3H), 2.55-2.60 (m, 2H), 0.94-1.04 (m, 28H),

Step 5: Preparation of Compound 83

To a solution of compound 82 (1.6 g, 2.45 mmol) in DCM (100 mL) wasbubbled with O₃ at −78° C. and the solution was stirred at the sametemperature for 3 h. To the solution was added 1 ml of Me₂S followed byaddition of NaBH₄ (92.5 mg, 2.45 mmol) at room temperature. The mixturewas stirred overnight. The solution was washed with H₂O and the solventwas removed to give a crude product which was purified by silica gelcolumn chromatography (hexane:EtOAc=1:1) to give compound 83 (1.0 g,62.1%).

Step 6: Preparation of Compound 84

A solution of MsCl (0.349 g, 3.04 mmol) in anhydrous CH₂Cl₂ (3 mL) wasadded dropwise to a solution of nucleoside 83 (1.0 g, 1522 mmol) inanhydrous pyridine (5.0 mL) at room temperature. After stirring for 12h, methanol (5.0 mL) was added and the resulting mixture was evaporatedto dryness under reduced pressure. The residue was co-evaporated withanhydrous toluene (2×5 mL) then dissolved in CH₂Cl₂ (50 mL). Thesolution was washed with saturated aqueous NaHCO₃ (2×25 mL). Thecombined aqueous phase was extracted with CH₂Cl₂ (50 mL). The combinedorganic phase was dried (Na₂SO₄) and solvent was evaporated to drynessunder reduced pressure to give compound 84 which was used for the nextreaction without further purification.

Step 7: Preparation of Compound 85

To a stirred suspension of NaH (180 mg, 4.50 mmol) in anhydrous THF (10mL) was added a solution of compound 84 (1.0 g, 1.50 mmol) in THF (5 mL)at 0° C. After stirring at room temperature for 2 h, ice-water (10 mL)was slowly added. CH₂Cl₂ (50 mL) was added and the separated organicphase was washed with saturated aqueous NaHCO₃ (2×20 mL). The combinedaqueous phase was extracted with CH₂Cl₂ (25 mL). The combined organicphase was dried (Na₂SO₄) and the solvent was evaporated to dryness underreduced pressure to provide 85 which was used for the next reactionwithout further purification.

Step 8: Preparation of Compound 86

To a stirred solution of compound 85 (1.0 g, 1.55 mmol) in anhydrousmethanol (50 mL) was added NaOMe (0.5 g, 9.26 mmol) and the solution wasstirred at room temperature for 20 h. The solution was filtered and thefiltrate was evaporated to give crude product 86.

Step 9: Preparation of Compound 87

To a stirred solution of compound 86 (0.8 g, 1.49 mmol) in anhydrousmethanol (30 mL) was added NH₄F (550 mg, 14.9 mmol) and the mixture washeated at reflux for 10 h. The mixture was filtered and the filtrate wasevaporated to give a crude product which was purified by silica gelcolumn chromatography (CH₂Cl₂:MeOH=20:1) to provide compound 87 (36.0mg, 21.05%). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.21 (s, 1H), 8.17 (s, 1H),7.29 (s, 2H), 6.26 (s, 1H), 5.90 (d, J=5.2 Hz, 1H), 5.04 (t, J=5.2 Hz,1H), 4.08-4.30 (m, 2H), 3.92-3.97 (m, 1H), 3.70-374 (m, 1H), 3.55-3.66(m, 2H), 2.98-3.05 (m, 1H), 2.41-2.49 (m, 1H). HRMS(TOF-ESI): Calc. ForC₁₂H₁₆N₅O₄, 294.1197. found 294.1194.

Example 17 Preparation of(5S,6R,8R,9R)-6-(6-amino-9H-purin-9-yl)-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-9-ol(94)

In the preparation of 94, it is possible to forego protection of the6-amino-purine, which means that 94 can be prepared from adenine (78)using a seven-step sequence.

Step 1: Preparation of Compound 88

To a solution of compound 78 (30.0 g, 112.0 mmol) in anhydrous pyridine(200 mL) was added TIPSCl (342.5 g, 113.5 mmol) at 0° C. The mixture wasstirred overnight and the solvent was removed under reduce pressure. Theresidue was dissolved in EtOAc (200 mL). The solution was washed withH₂O and the solvent was removed to give 88 which was used for nextreaction without further purification.

Step 2: Preparation of Compound 89

To a solution of CrO₃ (21.2 g, 212 mmol), anhydrous pyridine (32.42 mL,414 mmol) and Ac₂O (20.3 ml, 212 mmol) was added compound 88 (54.0 g,106 mmol) at 0° C. The mixture was stirred for 1 h and passed through ashort silica gel column. The solvent was removed and the residue wasco-evaporation with anhydrous toluene twice to give a crude compound 89which was used for the next reaction without further purification.

Step 3: Preparation of Compound 90

To a solution of compound 89 (31.0 g, 61.1 mmol) in THF (300 mL) wasadded a solution of allylmagnesium bromide (122 mL, 122 mmol) in THF (50mL) at −78° C. and the solution was stirred for 2 h at the sametemperature. The temperature was then raised to −10° C. and the reactionmixture was quenched by addition of NH₄Cl solution and the mixture wasextracted with DCM. The organic layer was dried over Na₂SO₄ and thesolvent was removed under reduced pressure. The residue was purificatedby silica gel column chromatography (hexane:EtOAc=3:1) to give product90 (8.0 g, 23.8%). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.12 (s, 1H), 8.10 (s,1H), 7.28 (s, 2H), 5.99 (s, 1H), 5.82-5.92 (m, 1H), 5.44 (s, 1H),5.12-5.19 (m, 1H), 5.01-5.08 (m, 1H), 4.56 (d, J=6.4 Hz, 1H), 3.96-4.04(m, 1H), 3.90-3.96 (m, 1H), 3.82-3.89 (m, 1H), 2.46-2.55 (m, 2H),0.94-1.04 (m, 28H),

Step 4: Preparation of Compound 91

To a solution of compound 90 (2.0 g, 3.64 mmol) in THF (50 mL) was addeda solution of BH₃ (1.82 mL, 18.2 mmol) at 0° C. and stirred for 2 h atthe same temperature. To the solution was added a mixture of H₂O₂ (4.13mL, 36.4 mmol) and NaOH (9.1 mL, 18.2 mmol). The resulting mixture wasstirred at room temperature overnight and extracted with DCM. Thesolvent was removed and the residue was purified by silica gel columnchromatography (hexane:EtOAc=1:1) to give product 91 (0.6 g, 29%). ¹HNMR (400 MHz, DMSO-d₆) δ: 8.13 (s, 1H), 8.12 (s, 1H), 7.30 (s, 2H), 5.94(s, 1H), 5.38 (s, 1H), 4.52-4.59 (m, 1H), 4.41-4.49 (m, 1H), 3.96-4.04(m, 1H), 3.95-4.05 (m, 2H), 3.75-3.84 (m, 1H), 1.75-1.80 (m, 1H),1.48-1.60 (m, 2H), 0.94-1.04 (m, 28H),

Step 5: Preparation of Compound 92

A solution of MsCl (0.058 g, 0.51 mmol) in anhydrous CH₂Cl₂ (5.0 mL) wasadded dropwise to a solution of nucleoside 91 (0.24 g, 0.42 mmol) inanhydrous pyridine (5.0 mL) at room temperature. After stirring for 12h, methanol (5.0 mL) was added and the resulting mixture was evaporatedto dryness under reduced pressure. The residue was co-evaporated withanhydrous toluene (2×5 mL). The residue was dissolved in CH₂Cl₂ (50 mL)and the solution was washed with saturated aqueous NaHCO₃ (2×25 mL). Thecombined aqueous phase was extracted with CH₂Cl₂ (50 mL). The combinedorganic phase was dried (Na₂SO₄) and the solvent was evaporated todryness under reduced pressure to give crude product 92 which was usedfor the next reaction without further purification.

Step 6: Preparation of Compound 93

To a stirred suspension of NaH (112 mg, 2.79 mmol) in anhydrous THF wasadded a solution of compound 92 (0.45 g, 0.697 mmol) in THF dropwise at0° C. After stirring at room temperature for 2 h, ice-water (10 mL) wasslowly added and the mixture was diluted with CH₂Cl₂. The separatedorganic phase was washed with saturated aqueous NaHCO₃ (2×20 mL). Thecombined aqueous phase was extracted with CH₂Cl₂ (25 mL) and thecombined organic phase was dried (Na₂SO₄) and the solvent was evaporatedto dryness under reduced pressure to provide 93 (330 mg, 86.1%) for thenext reaction without further purification.

Step 7: Preparation of Compound 94

To a stirred solution of compound 93 (0.25 g, 0.45 mmol) in anhydrousmethanol (20 mL) was added NH₄F (200 mg, 5.4 mmol) and the mixture washeated at reflux for 10 h. The solvent was evaporated and the residuewas purified by silica gel column chromatography (CH₂Cl₂:MeOH=20:1) togive 94 (53.4 mg, 38.7%). ¹H NMR (400 MHz, DMSO-d₆) δ: 8.26 (s, 1H),8.14 (s, 1H), 7.28 (s, 2H), 6.02 (s, 1H), 5.69 (d, J=5.2 Hz, 1H), 5.07(t, J=5.2 Hz, 1H), 4.09 (t, J=5.2 Hz, 1H), 3.72-3.79 (m, 1H), 3.60-3.69(m, 3H), 3.18-3.24 (m, 1H), 2.29-2.34 (m, 1H), 1.74-1.82 (m, 2H),1.62-1.64 (m, 1H). HRMS (TOF-ESI): Calc. For C₁₃H₁₈N₅O₄ ⁺, 308.1359.found 308.1347.

B. Preparation of 2′-Spiro-Ribo-Adenine Analogs

Example 18 Preparation of(4R,5R,7R,8R)-5-(6-amino-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol(100)

Step 1. Preparation of Compound 95

A mixture of N⁶-benzoyladenine (3.14 g, 13.19 mmol) in HMDS (30 mL) with(NH₄)SO₄ (50 mg) was heated at 140° C. for 4 h. Solvent was removed andthe residue was dissolved in MeCN (50 mL). To the solution was added asolution of sugar 37 in MeCN (30 mL). To the resulting solution wasadded SnCl₄ (39.57 mml, 1M, 39.57 mL) in CH₂Cl₂ at 0° C. and thesolution was stirred at 60° C. for 4 h. The reaction solution was cooledto room temperature and poured into ice-water, excess NaHCO₃ and EtOAc(200 mL) with stirring. Organic solution was washed with brine and driedover Na₂SO₄. Solvent was removed and the residue was purified by silicagel column chromatography (10-70% EtOAc in hexane) to give compound 95as foam (1.95 g, 41%). ¹H NMR (400 MHz, CDC₃) δ: 9.04 (s, 1H), 8.89 (s,1H), 8.26 (s, 1H), 7.35-8.20 (m, 20H), 6.53 (d, J=7.6 Hz, 1H), 5.29 (m,1H), 4.68-5.00 (m, 4H), 2.99 (m, 1H), 2.65 (m, 1H). m/z: 724 (M+1).

Step 2. Preparation of Compound 96

A solution of compound 95 (1.9 g, 2.63 mmol) in methanolic ammonia (7N,50 mL) was stirred at room temperature for 24 h. Solvent was removed andthe residue was purified by silica gel column chromatography (0-15% MeOHin CH₂Cl₂) to give compound 96 (0.47 g, 53%) as white solid. LC-MS(ESI): 308 [M+H]⁺.

Step 3. Preparation of Compound 97

To a solution of compound 96 (0.58 g, 1.84 mmol) in pyridine (50 mL)were added TIPSCl dropwise and the mixture was stirred at 0° C. for 2 hand room temperature for 16 h. Water (10 mL) was added and the mixturewas concentrated to dryness under reduced pressure and the residue wasdissolved in EtOAc (100 mL). The solution was washed with brine anddried over Na₂SO₄. Solvent was removed and the residue was purified bysilica gel column chromatography (0-10% MeOH in CH₂Cl₂) to give compound97 (0.65 g, 77%) as white foam. ¹H NMR (400 MHz, CDCl₃) δ: 8.31 (s, 1H),7.87 (s, 1H), 5.97 (s, 1H), 5.70 (m, 1H), 5.56 (s, 2H), 5.04 (d, J=8.0Hz, 1H), 4.85 (d, J=10.4 Hz, 1H), 4.48 (d, J=17.2 Hz, 1H), 4.30 (m, 1H),4.12 (m, 1H), 4.03 (dd, J=3.2, 12.4 Hz, 1H), 3.20 (s, 1H), 2.27 (m, 1H),2.05 (m, 1H), 1.20 (m, 4H), 1.07 (m, 28H). LC-MS (ESI): 550 [M+H]⁺.

Step 4. Preparation of Compound 98

To a solution of compound 97 (0.25 g, 0.45 mmol) in CH₂Cl₂ (10 mL) andpyridine (1 mL) was added BzCl (3 eq) and the solution was stirred at 0°C. for 3 h and room temperature for 2 h. To the solution was added 30%NH₄OH (1 mL) slowly. The mixture was stirred at room temperature for 20min. EtOAc (100 mL) was added and the solution was washed with brine anddried over Na₂SO₄. Solvent was evaporated and the residue wasco-evaporated with toluene twice. The residue was purified by silica gelcolumn chromatography (0-8% MeOH in CH₂Cl₂) to give compound 98 (0.10 g,34%) as white solid. LC-MS (ESI): 654 [M+H]⁺.

Step 5. Preparation of Compound 6

To a solution of compound 98 (0.12 g, 0.19 mmol) in THF (5 mL) andt-BuOH (5 mL) and water (1 mL) was added 0.025% OsO₄ in t-BuOH (0.5 mL)and NMO (50%, 0.3 mL). The solution was stirred at room temperature for20 h. Solvent was evaporated and the residue was co-evaporated with EtOHtwice. The residue was dissolved in THF (10 mL) and water (1 mL). To thesolution was added NaIO₄ (10 eq) and the mixture was stirred at roomtemperature for 5 h. Solid was filtered and the filtrate was dilutedwith EtOAc (100 mL). The organic solution was washed with brine anddried over Na₂SO₄. The solvent was evaporated and the residue wasdissolved in EtOAc (5 mL) and EtOH (5 mL). To the solution was addedNaBH₄ (5 eq) and the mixture was stirred at 0° C. for 3 h. The mixturewas poured into EtOAc (100 mL) and the solution was washed with brineand dried over Na₂SO₄. Solvent was evaporated and the residue waspurified by silica gel column chromatograph (0.8% MeOH in CH₂Cl₂) togive compound 99 (0.10 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ: 9.12 (s, 1H),8.79 (s, 1H), 8.35 (s, 1H), 7.48-8.04 (m, 5H), 6.18 (s, 1H), 4.85 (d,J=8.4 Hz, 1H), 4.32 (dd, J=4.4, 12.8 Hz, 1H), 4.24 (m, 1H), 4.07 (dd,J=2.8, 12.4 Hz, 1H), 3.74 (m, 2H), 3.65 (s, 1H), 3.28 (brs, 1H), 1.86(m, 1H), 1.42 (m, 1H), 1.06-1.20 (m, 28H). LC-MS (ESI): 658 [M+H]⁺.

Step 6. Preparation of Compound 100

To a solution of compound 99 (0.20 g, 0.30 mmol) in CH₂Cl₂ (10 mL) andpyridine (1 mL) was added MsCl (0.1 mL) and the solution was stirred at0° C. for 2 h.

Water (5 mL) was added followed by addition of EtOAc (100 mL). Themixture was washed with brine and dried over Na₂SO₄. Solvent was removedand the residue was co-evaporated with toluene twice. The resultingmesylate was dissolved in dry THF (10 mL). To the solution was added NaH(100 mg, 2.5 mmol) and the mixture was stirred at room temperature for 3h. EtOAc (100 mL) was added and the mixture was washed with brine anddried over Na₂SO₄. Solvent was removed and the residue was dissolved inMeOH (10 mL). To the solution was added butylamine (1 mL) and NH₄F (100mg) and the mixture was refluxed for 5 h. Solvent was removed and theresidue was purified by silica gel column chromatography (0-15% MeOH inCH₂Cl₂) to give compound 100 as white solid (0.04 g, 45.5%). ¹H NMR (400MHz, DMSO-d₆) δ: 8.37 (s, 1H), 8.18 (s, 1H), 7.35 (brs, 2H), 6.25 (s,1H), 5.51 (d, J=8.0 Hz, 1H, OH), 5.14 (t, J=5.6 Hz, 1H, OH), 4.37 (m,2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.61 (m, 1H), 2.44 (m, 1H), 2.12 (m,1H). LC-MS (ESI): 294 [M+H]⁺

Example 19 Preparation of(5R,6R,8R,9R)-6-(6-amino-9H-purin-9-yl)-8-(hydroxymethyl)-1,7-dioxaspiro[4.4]nonan-9-ol(5)

Step 1. Preparation of Compound 97

To a solution of compound 96 (0.58 g, 1.84 mmol) in pyridine (50 mL)were added TIPSCl dropwise and the mixture was stirred at 0° C. for 2 hand room temperature for 16 h. Water (10 mL) was added and the mixturewas evaporated. The residue was dissolved in EtOAc (100 mL) and thesolution was washed with brine and dried over Na₂SO₄. Solvent wasremoved and the residue was purified by silica gel column chromatography(0-10% MeOH in CH₂Cl₂) to give compound 97 as white foam. ¹H NMR (400MHz, CDCl₃) δ: 98.31 (s, 1H), 7.87 (s, 1H), 5.97 (s, 1H), 5.71 (m, 1H),5.56 (brs, 2H), 5.045 (d, J=8.0 Hz, 1H), 4.85 (d, J=10.04 Hz, 1H), 4.47(d, J=17.2 Hz, 1H), 4.30 (m, 1H), 4.12 (m, 1H), 4.03 (dd, J=3.2, 12.4Hz, 1H), 3.22 (s, 1H), 2.30 (m, 1H), 2.07 (m, 1H), 1.00-1.25 (m, 28H).LC-MS (ESI): 550 [M+H]⁺.

Step 2. Preparation of Compound 101

To a solution of compound 97 (0.10 g, 0.18 mmol) in THF (10 mL) wasadded BH₃—SMe₂ (0.3 mL) and the solution was stirred at 0° C. for 3 h.To the solution was added H₂O₂ (1 mL) then 2 N NaOH (1 mL) and themixture was stirred at room temperature for 3 h. EtOAc (100 mL) wasadded and the organic solution was washed with brine and dried overNa₂SO₄. Solvent was removed and the residue was purified by silica gelcolumn chromatography (0-10% MeOH in CH₂Cl₂) to give compound 101 (0.02g, 24%). ¹H NMR (400 MHz, CDCl₃) δ: 8.28 (s, 1H), 8.04 (s, 1H), 6.08 (s,1H), 5.99 (brs, 2H), 4.81 (d, J=8.0 Hz, 1H), 4.26 (m, 1H), 4.15 (m, 1H),4.05 (m, 1H), 3.72 (brs, 1H), 3.38 (m, 2H), 1.63 (m, 1H), 1.37 (m, 1H),0.93-1.21 (m, 28H). LC-MS (ESI): 568 [M+H]⁺.

Step 3. Preparation of Compound 102

To a solution of compound 101 (0.09 g, 0.16 mmol) in CH₂Cl₂ (10 mL) andpyridine (1 mL) was added TMSCl (0.1 mL) and the solution was stirred at0° C. for 1 h. To the solution was added BzCl (0.1 mL) and the resultingsolution was stirred at 0° C. for 1 h and room temperature for 4 h. 30%NH₄OH (3 mL) was added and the solution was stirred at room temperaturefor 1 h. EtOAc (100 mL) was added and the solution was washed with brineand dried over Na₂SO₄. Solvent was removed and the residue was dissolvedin MeOH (10 mL). To the solution was added 30% NH₄OH (1 mL) and thesolution was stirred at room temperature for 1 h. Solvent was removedand the residue was purified by silica gel chromatography (0-10% MeOH inCH₂Cl₂) to give compound 102 (0.07 g, 62%) as foam. ¹H NMR (400 MHz,CDCl₃) δ: 9.24 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 7.50-8.03 (m, 5H),6.15 (s, 1H), 5.29 (s, 1H), 4.84 (d, J=7.6 Hz, 1H), 4.26 (dd, J=4.8,12.4H, 1H), 4.16 (m, 1H), 4.04 (dd, 3.2, 12.4 Hz, 1H), 3.53 (brs, 1H),5.37 (m, 2H), 1.63 (m, 1H), 1.31 (m, 1H), 0.98-1.21 (m, 28H). LC-MS(ESI): 672 [M+H]⁺.

Step 4. Preparation of Compound 103

To a solution of compound 102 (0.07 g, 0.10 mmol) in CH₂Cl₂ (10 mL) andpyridine (1 mL) was added MsCl at 0° C. and the solution was stirred atroom temperature for 3 h. To the solution was added water (10 mL) andthe mixture was extracted with EtOAc (100 mL). Organic solution wasdried over Na₂SO₄. Solvent was removed to give a crude mesylate whichwas dissolved in THF (10 mL). To the solution was added NaH (60% inmineral oil, 100 mg) and the mixture was stirred at room temperature for2 h. Water (2 mL) was added slowly then the mixture was extracted withEtOAc (100 mL). The organic solution was washed with brine and driedover Na₂SO₄. Solvent was removed to give protected 2′-spironucleosidewhich was dissolved in MeOH (10 mL). To the solution was added NH₄F (200mg) and BuNH₂ (1 mL) and the mixture was refluxed for 5 h. Solvent wasremoved and the residue was purified by silica gel column chromatography(0-15% MeOH in CH₂Cl₂) to give compound 103 (20 mg, as white solid. ¹HNMR (400 MHz, CD₃OD) δ: 8.55 (s, 1H), 8.19 (s, 1H), 6.08 (s, 1H), 4.38(d, J=9.6 Hz, 1H), 3.84-4.12 (m, 5H), 1.90 (m, 2H), 1.78 (m, 1H), 1.30(m, 1H). LC-MS (ESI): 308 [M+H]⁺.

V. Preparation of 2′-Spiro-Ribo-(6-Substituted-Purine) Analogs

6-Substituted purine nucleosides can be prepared from commonintermediate, 6-chloropurine analogs as shown in the following scheme.

Treatment of compound 67 with methanolic ammonia gave free nucleoside104. Selective protection of 3′,5′-diol of nucleoside with TIPSClfollowed by N-benzoylation provided intermediate 106. Ozonolysis ofcompound 106 followed by reduction of the resulting aldehyde gavecompound 107. Selective mesylation of compound 108 followed bycyclization in the presence of base, such as NaH, or NaHMDS, afforded2′-oxetanyl compound 109. Treatment of compound 109 with TBAF providedthe key intermediate for the 6-substitution. Treatment of 6-chloropurineintermediate with alcohol or amine or other nucleophile provided6-substituted 2′-spironucleoside.

Example 20 Preparation ofN-(6-chloro-9-((4R,5R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-5-yl)-9H-purin-2-yl)benzamide(110) Step 1: Preparation of Compound 104

To a solution of compound 67 (6.5 g, 0.01 mol) in dry MeOH (50 mL) wasadded saturated NH₃/MeOH solution (50 mL). The mixture was stirred atroom temperature overnight. The solvent was evaporated and the residuewas recrystallized in MeOH/EtOAc to give the pure desired compound 104(2.3 g, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (s, 1H), 6.98 (s, 2H), 5.86 (s, 1H),5.54-5.60 (m, 1H), 5.37 (d, J=6.4 Hz, 1H), 5.07 (t, J=5.2 Hz, 1H), 5.07(s, 1H), 4.66 (dd, J=10.4 Hz, 2.0 Hz, 1H), 4.48 (d, J=17.2 Hz, 2.0 Hz,1H), 4.20-4.24 (m, 1H), 3.85-3.88 (m, 1H), 3.76-3.79 (m, 1H), 3.64-3.69(m, 1H), 2.21 (dd, J=14.8, 6.8 Hz, 1H), 1.95 (dd, J=4.8 Hz, 7.2 Hz, 1H).LC-MS (ESI): 341 [M+H]+

Step 2: Preparation of Compound 105

Compound 104 (0.5 g, 1.4 mmol) in anhydrous pyridine (10 mL) at 0° C.was stirred for 30 min until the solid was dissolved completely. To thesolution was added TIPSCl (0.7 g, 2.2 mmol) dropwise and the stirringwas continued at 0° C. for 3 h. Water (2 mL) was added and the solventwas removed under reduced pressure. The mixture was dissolved in EtOAcand the solution was washed with water, brine, and dried over MgSO₄.Solvent was evaporated to give crude compound 105 (0.75 g, yield: 88%).LC-MS (ESI): 584 [M+H]⁺.

Step 3: Preparation of Compound 106

To a solution of compound 105 (0.75 g, 1.2 mmol) in a mixture of drypyridine (15 mL) and CH₂Cl₂ (30 mL) was added BzCl (0.4 mL) and thesolution was stirred at room temperature for 2 h. Water (10 mL) wasadded and the solution was evaporated. The residue was dissolved inEtOAc (200 mL) and the organic phase was washed with brine and driedover MgSO₄. Solvent was removed and the residue was purified by silicagel column chromatography (0-2% MeOH in CH₂Cl₂) to give compound 106 asfoam (0.8 g, yield: 97%). ¹H NMR (400 MHz, CDCl₃): δ 8.79 (s, 1H), 8.05(d, J=7.6 Hz, 2H), 7.51 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 2H), 7.10(s, 1H), 5.95 (s, 1H), 5.62-5.73 (m, 1H), 5.00 (d, J=8.0 Hz, 1H), 4.77(d, J=9.2 Hz, 1H), 4.30-4.35 (m, 2H), 4.05 (s, 1H), 3.93 (dd, J₁=12.4Hz, J2=2.4 Hz, 1H), 3.30 (bs, 1H), 2.32-2.38 (m, 1H), 2.01-2.12 (m, 1H),1.12-1.32 (m, 2H), 0.85-0.98 (m, 28H); LC-MS (ESI): 688 [M+H]⁺.

Step 4: Preparation of Compound 107

To a solution of compound 106 (0.8 g, 1.1 mmol) in DCM (100 mL) in a 250mL three-neck flask was bubbled with O₃ at −78° C. After color ofreaction solution became blue, the reaction mixture was stirred foradditional 5 min. Excess O₃ was removed by bubbling N₂ into the reactionmixture. EtOAc (30 mL) and ethanol (30 mL) was added. To the resultingsolution was added NaBH₄ (300 mg) and the mixture was stirred at roomtemperature for additional 2 h. Additional EtOAc (300 mL) was added andthe solution was washed with brine, water, and dried over MgSO₄. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography (0-2% MeOH in DCM) to give compound 107 (0.40 g, 50%) asfoam. ¹H NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H), 8.60 (s, 1H), 7.93 (d,J=7.6 Hz, 2H), 7.61 (t, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 2H), 6.25 (s,1H), 4.56 (d, J=7.6 Hz, 2H), 4.40 (s, 1H), 4.10-4.31 (m 3H), 4.02-4.12(m, 2H), 3.75-3.85 (m, 2H), 2.01-2.12 (m, 1H), 1.35-1.42 (m, 1H),1.02-1.21 (m, 28H). LC-MS (ESI): 692 [M+H]⁺.

Step 5: Preparation of Compound 108

To a solution of compound 107 (3.2 g, 4.5 mmol) in DCM (50 mL) was addedtriethylamine (3 mL), then MsCl (1 g, 8.8 mmol) was added and themixture was stirred at 0° C. for 2 h. DCM (150 mL) was added to thesolution and the organic phase was washed with brine, water, and driedover MgSO₄. The solvent was evaporated and the residue was purified bysilica gel column chromatography (0-2% MeOH in DCM) to give compound 108as foam (3.3 g, yield: 94%). ¹H NMR (400 MHz, CDCl₃): δ 8.76 (s, 1H),8.36 (s, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.61 (t, J=7.6 Hz, 1H), 7.50 (d,J=7.6 Hz, 2H), 6.15 (s, 1H), 4.90 (bs, 1H), 4.59 (d, J=7.6 Hz, 1H), 4.40(bs, 1H), 4.34 (dd, J₁=12.8 Hz, J₂=4 Hz, 1H), 4.12-4.15 (m, 1H), 4.02(dd, J₁=12.8 Hz, J₂=2.8 Hz, 1H), 3.28 (s, 1H), 2.98 (s, 3H), 2.03-2.09(m, 1H), 1.56-1.66 (m, 1H), 1.02-1.21 (m, 28H). LC-MS (ESI): 770 [M+H]⁺.

Step 6: Preparation of Compound 13

To a solution of compound 108 (2.8 g, 3.6 mmol) in THF (20 mL) was added2M NaHMDS (5 mL, 10 mmol) in one portion at −20° C. The reaction mixturewas stirred for 2 h, during which the temperature rose to 0° C.gradually. The reaction mixture was diluted with EtOAc (200 mL) andwashed with a solution of ammonium chloride three times. The solutionwas concentrated in vacuo to give crude compound 109 which was used forthe next reaction without further purification. LC-MS (ESI): 692 [M+H]⁺.

Step 7: Preparation of 110

To a solution of compound 109 (2.4 g, 3.6 mmol) in THF (40 mL) was addedTBAF (1.2 g, 4.5 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. The solvent was evaporated and the residue waspurified by silica gel column chromatography (DCM/MeOH=60/1) to givecompound 110 (1.3 g, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.35 (s, 1H),8.78 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.50 (d,J=7.6 Hz, 2H), 6.28 (s, 1H), 5.45 (bs, 1H), 5.01 (bs, 1H), 4.41-4.45 (m,3H), 3.55-3.75 (m, 3H), 3.12-3.15 (m, 1H), 2.29-2.31 (m, 1H), 2.25-2.28(m, 1H)). LC-MS (ESI): 432 [M+H]⁺.

Example 21 Preparation of(4R,5R,7R,8R)-5-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol(111)

110 (800 mg, 1.85 mmol) in cyclopropylamine (10 mL) was stirred at roomtemperature for 24 h. To the solution were added MeOH (10 mL) and 5.4 MNaOMe (1.71 mL, 9.26 mmol) and the resulting mixture was stirred at roomtemperature for 15 h. The mixture was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (0 to 20% MeOHin CH₂Cl₂) to give 6-cyclopropylamino-nucleoside 111 (500 mg, 76%) as awhite solid. ¹H NMR (400 MHz, CD₃OD) δ: 8.02 (s, 1H), 6.21 (s, 1H), 4.53(m, 2H), 4.43 (d, 1H, J=8.8 Hz), 3.96 (m, 1H), 3.82-3.77 (m, 2H), 2.91(m, 1H), 2.56 (m, 1H), 2.27 (m, 1H), 0.83 (m, 2H), 0.60 (m, 2H). LCMS(ESI): 349 (M+H)+.

Example 22(4R,5R,7R,8R)-5-(2-amino-6-(azetidin-1-yl)-9H-purin-9-yl)-7-(hydroxymethyl)-1,6-dioxaspiro[3.4]octan-8-ol(112) was prepared

¹H NMR (400 MHz, CD₃OD) δ: 8.06 (s, 1H), 6.22 (s, 2H), 4.54 (m, 4H),4.41 (m, 2H), 3.97 (m, 1H), 3.82 (m, 2H), 2.54 (m, 1H), 2.50 (m, 2H),2.28 (m, 1H). LCMS (ESI): 349 (M+H)⁺.

VI. Preparation of 2′-Spiro-Phosphoramidate Analogs

Examples 23-27 describe procedures for converting a corresponding-2′-spiro-nucleoside to its corresponding phosphoramidate, as shown bythe following equation.

Ex Starting Material

B Product 23 70

2-NH₂-6-OMe-purine 113 24 32

Uracil 114 25 36

Uracil 115 26 44

Uracil 116 27 48

Uracil 117

Example 23 Preparation of (2S)-methyl2-(((((4R,5R,7R,8R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,113

To a pre-cooled solution of phenyl dichlorophosphate (2.1 g, 9.96 mmol)in CH₂Cl₂ (40 mL) was added L-alanine methyl ester hydrochloride (1.39g, 9.96 mmol) followed by addition of Et₃N (2.02 g, 19.92 mmol) inCH₂Cl₂ (5 mL) slowly and the mixture was stirred at −78° C. for 1 h thenat room temperature for 16 h. Solvent was evaporated and the residue wasfiltered with Et₂O (20 mL). Solvent was evaporated to givechlorophosphate reagent which was dissolved in CH₂Cl₂ (10 mL) for thenext reaction. To a mixture of compound 70 (0.02 g, 0.06 mmol) in CH₂Cl₂(15 mL) were added N-methylimidazole (0.2 mL) and a solution of abovereagent (0.5 mL, 0.5 mmol), and the resulting mixture was stirred atroom temperature for 3 h. EtOAc (100 mL) was added and the mixture waswashed with water, 1N HCl, aqueous NaHCO₃ and brine, sequentially.Organic solution was dried over Na₂SO₄ and evaporated, and the residuewas purified by silica gel column chromatography (0-8% MeOH in CH₂Cl₂)to give compound 113 (0.01 g, 41%). ¹H NMR (400 MHz, CDCl₃) δ: 7.69,7.61 (ss, 1H), 7.25 (m, 5H), 6.18 (ss, 1H), 5.08 (ss, 2H), 4.60 (m, 3H),4.35 (m, 1H), 4.06 (ss, 3H), 3.90 (m, 3H), 3.60 (ss, 3H), 3.35 (m, 1H),2.66 (m, 1H), 2.18 (m, 1H), 1.32 (m, 3H). LC-MS (ESI): 565 [M+H]⁺.

Example 24 Preparation of (2S)-methyl2-(((((5S,6R,8R,9R)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-9-hydroxy-1,7-dioxaspiro[4.4]nonan-8-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,114

Compound 114 is prepared from 32 using a procedure analogous to Example23. Data for 114: ¹H NMR (400 MHz, CDCl₃) δ: 8.75 (s, 1H), 7.60, 7.52(dd, J=8.0 Hz, 1H), 7.24 (m, 5H), 6.05, 6.04 (ss, 1H), 5.65, 5.58 (d,J=8.0, 1H), 4.35 (m, 2H), 4.00 (m, 4H), 3.80 (m, 4H), 3.72, 3.70 (ss,3H), 2.39 (m, 1H), 1.90 (m, 2H), 1.72 (m, 1H), 1.36 (m, 3H). LC-MS(ESI): 525 [M+H].

Example 25 Preparation of (2S)-methyl2-(((((4S,5R,7R,8R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,115

Compound 115 is prepared from 36 using a procedure analogous to Example23.

Data for 115: ¹H NMR (400 MHz, CDCl₃) δ: 8.18 (s, 1H), 7.30 (m, 6H),6.12 (ss, 1H), 5.62 (m, 1H), 4.07, 4.113.80 (m, 8H), 3.74, 3.72 (ss,3H), 3.17 (m, 1H), 2.60 (m, 1H), 1.37 (d, J=7.2 Hz, 3H). LC-MS (ESI):512 [M+H]⁺.

Example 26 Preparation of (2S)-methyl2-(((((5R,6R,8R,9R)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-9-hydroxy-1,7-dioxaspiro[4.4]nonan-8-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,116

Compound 116 is prepared from 44 using a procedure analogous to Example23. Data for 116: ¹H NMR (400 MHz, CDCl₃) δ: 8.51, 8.40 (ss, 1H), 7.48,7.42 (d, 8.0 Hz, 1H), 7.29 (m, 5H), 5.98 (s, 1H), 5.62 (m, 1H), 4.48 (m,2H), 3.95 (m, 6H), 3.73, 3.72 (ss, 3H), 2.83 (m, 1H), 1.95 (m, 2H), 1.69(m, 1H), 1.37 (m, 3H). LC-MS (ESI): 526 [M+H]⁺.

Example 27 Preparation of (2S)-methyl2-(((((4R,5R,7R,8R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-8-hydroxy-1,6-dioxaspiro[3.4]octan-7-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,117

Compound 117 is prepared from 48 using a procedure analogous to Example23.

Data for 117: ¹H NMR (400 MHz, CDCl₃) δ: 9.15, 9.07 (ss, 1H), 7.26 (m,7H), 6.19, 6.15 (ss, 1H), 5.65 (m, 1H), 4.50 (m, 4H), 3.95 (m, 4H),3.72, 3.70 (ss, 3H), 3.42 (s, 1H), 2.75 (m, 1H), 2.46 (m, 1H), 1.35 (m,3H). LC-MS (ESI): 512 [M+H]⁺.

VII. General Synthesis of Chiral Phosphoramidates

Example 29 General Procedure for preparation of chiral 2′-oxetanylnucleoside phosphoramidates

To a solution of the oxetanyl nucleoside 70 (360 mg, 1.11 mmol) inanhydrous THF (15 mL) was added 1.7 M t-butylmagnesium chloride in THF(1.31 mmol) dropwise under ice-water bath. The resulting suspension wasstirred at room temperature for 30 min and the chiral pentafluorophenylphosphoramidate reagent (R=neopentyl (^(neo)Pen), 1.67 mmol) in THF (10mL) was added over 10 min by which time, the mixture became a clearsolution. The mixture was stirred at room temperature for 4 h anddiluted with EtOAc, (200 mL). The solution was washed with NH₄Clsolution (30 mL x 3), and dried with sodium sulfate. Solvent wasevaporated and the residue was purified by silica gel columnchromatography (0 to 3% MeOH in CH₂Cl₂) to give the oxetanyl nucleosidephosphoramidate (79%, R=neopentyl) as a white solid.

Com- P- pound Chirality No. (R_(P)/S_(P)) Ar R Analytical data 118 S_(P)Ph ^(i)Pr^(a) ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.69 (s, 1H), 7.32-7.12(m, 5H), 6.16 (s, 1H), 5.09 (s, 2H), 4.96 (m, 1H), 4.73 (dd, 1H, J =8.8, 10.4 Hz), 4.61- 4.53 (m, 3H), 4.33 (m, 1H), 4.06 (s, 3H), 3.98-3.90(m, 2H), 3.70 (dd, 1H, J = 9.2, 11.2 Hz), 3.24 (d, 1H, J = 10.0 Hz),2.68 (m, 1H), 2.17 (m, 1H), 1.30 (d, 3H, J = 7.2 Hz), 1.18 (2d, 6H, J =6.4 Hz). ³¹P NMR (162 MHz) δ (ppm) 4.16. LC-MS (ESI): 593 [M + H]⁺. 119R_(P) Ph ^(i)Pr^(a) ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.62 (s, 1H),7.32-7.12 (m, 5H), 6.20 (s, 1H), 5.11 (s, 2H), 4.97 (m, 1H), 4.6-4.53(m, 4H), 4.38 (m, 1H), 4.07 (s, 3H), 3.99-3.92 (m, 2H), 3.85 (t, 1H, J =11.2 Hz), 3.61 (bs, 1H), 2.62 (m, 1H), 2.15 (m, 1H), 1.98 (bs, 1H), 1.29(d, 3H, J = 6.8 Hz), 1.20 (t, 3H, J = 6.4 Hz). ³¹P NMR (162 MHz) δ (ppm)4.74. LC-MS (ESI): 593 (M + H)⁺ 120 S_(P) Ph ^(neo)Pen^(b) ¹H NMR (400MHz, CDCl₃) δ (ppm) 7.69 (s, 1H), 7.32-7.12 (m, 5H), 6.16 (s, 1H), 5.07(s, 2H), 4.72 (t, 1H, J = 10.0 Hz), 4.60-4.52 (m, 3H), 4.34 (m, 1H),4.07-4.01 (m, 4H), 3.92 (m, 1H), 3.82 (d, 1H, J = 10.4 Hz), 3.70 (m,1H), 3.15 (d, 1H, J = 10.0 Hz), 2.68 (m, 1H), 2.17 (m, 1H), 1.35 (d, 3H,J = 6.8 Hz), 0.89 (s, 9H). ³¹P NMR (162 MHz) δ (ppm) 4.11. LC- MS (ESI):621 [M + H]⁺. 121 R_(P) Ph ^(neo)Pen^(b) ¹H NMR (400 MHz, CDCl₃) δ (ppm)7.62 (s, 1H), 7.34-7.13 (m, 5H), 6.19 (s, 1H), 5.07 (s, 2H), 4.66-4.52(m, 4H), 4.38 (m, 1H), 4.11-4.03 (m, 4H), 3.93 (m, 1H), 3.85-3.72 (m,3H), 3.42 (bs, 1H), 2.63 (m, 1H), 2.15 (m, 1H), 1.34 (d, 3H, J = 7.2Hz), 0.91 (s, 9H). ³¹P NMR (162 MHz) δ (ppm) 4.76. LC-MS (ESI): 621 [M +H]⁺. 122 S_(P) Ph ethyl ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.70 (s, 1H),7.32-7.14 (m, 5H), 6.17 (s, 1H), 5.10 (s, 2m), 4.72 (t, 1H, J = 9.2 Hz),4.59-4.54 (m, 3H), 4.35 (m, 1H), 4.15-4.09 (m, 5H), 4.00-3.91 (m, 2H),3.77 (dd, 1H, J = 9.6, 11.2 Hz), 3.36 (d, 1H, J = 10.4 Hz), 2.67 (m,1H), 2.18 (m, 1 h), 1.31 (d, 3H , J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz).³¹P NMR (162 MHz) δ (ppm) 4.08. LC- MS (ESI): 579 [M + H]⁺. 123S_(P)/R_(P) Np ^(neo)Pen^(b) ¹H NMR (400 MHz, CDCl₃) δ (ppm) 8.10 (m,1H), 7.82 (m, 1H), 7.69-7.63 (m, 2H), 7.49 (m, 3H), 7.36 (m, 1H), 6.15(ds, 1H), 5.08 and 5.04 (s, 2H), 4.84-4.60 (m, 2H), 4.54 (t, 2H, J = 7.6Hz), 4.40 (m, 1H), 4.11 (m, 1H), 4.04 (s, 3H), 3.93 (m, 2H), 3.79 (dd,1H, J = 1.6, 10.8 Hz), 3.64 (dd, 1H, J = 6.4, 10.0 Hz), 3.37 (broad ds,1H), 2.66 (m, 1H), 2.16 (m, 1H), 1.31 and 1.28 (s, 3H), 0.86 (s, 9H).³¹P NMR (162 MHz) δ (ppm) 5.041, 4.47. LC- MS (ESI): 671 [M + H]⁺. 124S_(P) Ph ^(i)Bu^(c) ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.71 (s, 1H),7.31-7.12 (m, 5H), 6.18 (s, 1H), 5.14 (s, 2H), 4.7 (t, 1H, J = 8.8 Hz),4.60-4.53 (m, 3H), 4.35 (m, 1H), 4.05 (s, 3H), 4.05-3.85 (m, 4H), 3.78(dd, 1H, J = 6.8, 10.4 Hz), 3.53 (d, 1H, J = 9.6 Hz), 2.66 (m, 1H), 2.17(m, 1H), 1.87 (m, 1H), 1.33 (d, 3H, J = 6.8 Hz), 0.88 and 0.86 (d, 6H, J= 1.6 Hz). ³¹P NMR (162 MHz) δ (ppm) 4.15. LC-MS (ESI): 607 [M + H]⁺.125 R_(P) Ph ^(i)Bu^(c) ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.61 (s, 1H),7.34-7.13 (m, 5H), 6.19 (s, 1H), 5.05 (s, 2H), 4.68-4.52 (m, 4H), 4.37(m, 1H), 4.09-3.98 (m, 4H), 3.93-3.82 (m, 3H), 3.74 (t, 1H, J = 9.2 Hz),3.34 (d, 1H, J = 9.6 Hz), 2.62 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.32(d, 3H, J = 7.2 Hz), 0.89 (d, 6H, J = 6.4 Hz). ³¹P NMR (162 MHz) δ (ppm)4.74. LC-MS (ESI): 607 [M + H]⁺. 126 S_(P) Ph ^(n)Bu^(d) ¹H NMR (400MHz, CDCl₃) δ (ppm) 7.70 (s, 1H), 7.32-7.12 (m, 5H), 6.17 (s, 1H), 5.11(s, 2H), 4.71 (t, 1H, J = 6.8 Hz), 4.59-4.52 (m, 3H), 4.35 (m, 1H),4.11-3.91 (m, 7H), 3.81 (dd, 1H, J = 9.6, 11.6 Hz), 3.41 (d, 1H, J =10.0 Hz), 2.67 (m, 1H), 2.17 (m, 1H), 1.54 (m, 2H), 1.36-1.27 (m, 5H),0.87 (t, 3H, J = 7.6 Hz). ³¹P NMR (162 MHz) δ (ppm) 4.12. LC-MS (ESI):607 [M + H]⁺. 127 R_(P) Ph ^(n)Bu^(d) ¹H NMR (400 MHz, CDCl₃) δ (ppm)7.62 (s, 1H), 7.33-7.13 (m, 5H), 6.20 (s, 1H), 5.07 (s, 2H), 4.65-4.52(m, 4H), 4.37 (m, 1H), 4.12-3.88 (m, 6H), 3.93 (m, 1H), 3.79 (t, 1H, J =11.2 Hz), 3.43 (bs, 1H), 2.63 (m, 1H), 2.15 (m, 1H), 1.57 (m, 2H),1.38-1.29 (m, 5H), 0.96 (t, 3H, J = 7.2 Hz). ³¹P NMR (162 MHz) δ (ppm)4.70. LC- MS (ESI): 607 [M + H]⁺. 128 S_(P) Ph ^(c)Pen^(e) ¹H NMR (400MHz, CDCl₃) δ (ppm) 7.69 (s, 1H), 7.32-7.13 (m, 5H), 6.16 (s, 1H), 5.12(m, 1H), 5.07 (s, 2H), 4.73 (m, 1H), 4.60-4.53 (m, 3H), 4.34 (m, 1H),4.06 (s, 3H), 3.98-3.90 (m, 2H), 3.66 (dd, 1H, J = 9.6, 11.2 Hz), 3.17(d, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.80 (m, 2H), 1.68-1.52 (m, 6H),1.29 (d, 3H, J = 6.8 Hz). ³¹P NMR (162 MHz) δ (ppm) 4.18. LC-MS (ESI):619 [M + H]⁺. 129 R_(P) Ph ^(c)Pen^(e) ¹H NMR (400 MHz, CDCl₃) δ (ppm)7.62 (s, 1H), 7.33-7.13 (m, 5H), 6.20 (s, 1H), 5.16-5.13 (m, 3H),4.64-4.54 (m, 4H), 4.38 (m, 1H), 4.07 (s, 3H), 3.99-3.91 (m, 2H), 3.83(dd, 1H, J = 9.6, 11.6 Hz), 2.63 (m, 1H), 2.15 (m, 1H), 1.80 (m, 2H),1.71-1.55 (m, 6H), 1.28 (d, 3H, J = 6.8 Hz). ³¹P NMR (162 MHz) δ (ppm)4.76. LC-MS (ESI): 619 [M + H]⁺. 130 S_(P) Ph Bn^(f) ¹H NMR (400 MHz,CDCl₃) δ (ppm) 7.73 (s, 1H), 7.37-7.11 (m, 10H), 6.17 (s, 1H), 5.09 (s,2H), 5.07 (s, 2H), 4.75 (m, 1H), 4.58 (m, 3H), 4.40 (m, 1H), 4.09-4.01(m, 4H), 3.92 (m, 1H), 3.74 (t, 1H, J = 2.6 Hz), 3.36 (bs, 1H), 2.68 (m,1H), 2.19 (m, 1H), 1.28 (d, 3H, J = 7.2 Hz). ³¹P NMR (162 MHz) δ (ppm)4.27. LC-MS (ESI): 641 [M + H]⁺. 131 R_(P) Ph Bn^(f) ¹H NMR (400 MHz,CDCl₃) δ (ppm) 7.60 (s, 1H), 7.36-7.12 (m, 10H), 6.17 (s, 1H), 5.10 (d,2H, J = 1.2 Hz), 5.05 (s, 2H), 4.66 (m, 1H), 4.62-4.51 (m, 3H), 4.34 (m,1H), 4.13-4.03 (m, 4H), 3.89 (m, 1H), 3.74 (t, 1H J = 11.2 Hz), 3.31 (d,1H, J = 7.6 Hz), 2.63 (m, 1H), 2.14 (m, 1H), 1.31 (d, 3H, J = 7.2 Hz).³¹P NMR (162 MHz) δ (ppm) 4.64. LC-MS (ESI): 641 [M + H]⁺. Notes:^(a)iso-propyl. ^(b)neo-pentyl. ^(c)iso-butyl. ^(d)n-butyl.^(e)cyclopentyl. ^(f)benzyl.

VIII. Synthesis of Cyclophosphate Prodrugs Example 30 Preparation ofCompound 132

To a pre-cooled CH₂Cl₂ (2 mL) at −78° C. was added POCl₃ (0.07 mL, 0.74mmol) and neopentyl alcohol (0.74 mmol)) to give a solution to which,Et₃N (0.12 mL, 0.87 mmol) was added dropwise. The resulting mixture wasstirred at −78° C. for 3 h and the oxetanyl nucleoside 76 (70 mg, 0.22mmol) in THF (2 mL) and then Et₃N (0.24 mL, 1.74 mmol) were added in oneportion each. Then NMI (0.17 mL, 2.17 mmol) was added over 3 min. Theresulting mixture was stirred for 6 h during which the temperature roseto room temperature. The mixture was cooled to −78° C., treated withconcentrated HCl to pH 4, diluted with CH₂Cl₂ (10 mL). The organicsolution was washed with dilute HCl solution, dried with sodium sulfate,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 3% MeOH in CH₂Cl₂) to give the oxetanyl nucleosidecyclophosphate 132 as a diastereomeric mixture (6.5 mg, 5.5%) as asyrup.

By the same fashion, the isopropyl cyclophosphate (133) was obtained asa diastereomeric mixture as a syrup (6.7 mg, from 100 mg of the oxetanylnucleoside 76, 5%).

Cyclopentyl cyclophosphate 134 was also obtained as a diastereomericmixture as a syrup (30 mg from 150 mg of the oxetanyl nucleoside, 14%).

Com- pound P-chirality No. (R_(P)/S_(P)) R Analytical data 132 1:1mixture neopentyl ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7..71 (s, 1H), 6.21and 6.20 (m, 1H), 5.11 and 5.09 (s, 2H), 4.73 (m, 1H), 4.63-4.48 (m,3H), 4.29 (m, 1H), 4.07 and 4.06 (s, 3H), 3.91 (m, 1H), 3.70 (m, 2H),2,69 (m, 1H), 2.19 (m, 1H), 0.93 and 0.91 (s, 9H). ³¹P NMR (162 MHz) δ(ppm) 1.71, 1.62. LC-MS (ESI): 488 [M + H]⁺. 133 3.7:1 mixture isopropyl¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.63 and 7.62 (s, 1H), 6.06 and 6.02 (d,1H, J = 0.8 Hz), 5.65 and 5.34 (2s, 1H, J = 10.4, 9.6 Hz), 5.00-4.79 (m,3H), 4.67-4.32 (m, 4H), 4.13-4.04 (m, 4H), 2.81-2.65 (m, 1H), 2.41- 2.31(m, 1H), 1.51-1.42 (m, 6H). ³¹P NMR (162 MHz) δ (ppm) −2.58, −5.77.LC-MS (ESI): 428 [M + H]⁺. 134 4.7:1 mixture cyclopentyl ¹H NMR (400MHz, CDCl₃) δ (ppm) 7.64 (s, 1H), 6.07 and 6.03 (s, 1H), 5.66 and 5.24(d, 1H, J = 9.6 Hz), 5.51-5.07 (m, 1H), 5.06 and 4.87 (s, 2H), 4.68-4.42 (m, 4H), 4.15-4.07 (m, 4H), 2.82-2.66 (m, 1H), 2.42-2.32 (m, 1H),2.06-1.78 (m, 8H). ³¹P NMR (162 MHz) δ (ppm) −2.59, −5.74. LC-MS (ESI):454 [M + H]⁺.

IX. Preparation of 2′-Spiro-Analogs

Additional procedures (both non-stereo- and stereoselective) forpreparing phosphoramidates are disclosed in U.S. patent application Ser.No. 12/783,680 (US 2010/0298257), filed May 20, 2010 and Ser. No.13/076,552 (US 2011/0251152), filed on Mar. 31, 2011.

In addition of phosphoramidate analogs, cyclic phosphates are alsocontemplated. To that end, procedures for preparing cyclic phosphatesare disclosed in U.S. patent application Ser. No. 12/479,075 (US2010/0081628), filed on Jun. 5, 2009.

Procedures for preparing certain phosphorus-containing compounds aredisclosed in U.S. Pat. No. 4,816,570.

Procedures for preparing a 1,3,2-dioxaphosphinane-2-oxide are disclosedin U.S. Pat. No. 6,752,981 and US 2009/0209481.

Procedures for preparing a 4H-benzo[d][1,3,2]dioxaphosphin-2-oxide aredisclosed in U.S. Pat. No. 6,312,662.

Procedures for preparing certain 3′,5′-diacyl derivatives are disclosedin U.S. Pat. No. 7,754,699, see also U.S. Pat. No. 5,246,937 forexamples of diacyl derivatives.

Procedures for preparing aminoacyl derivatives are disclosed in U.S.Pat. Nos. 4,957,924 and 6,083,953.

Procedures for preparing a derivative comprised of—P(O)(O(CH₂)₁₋₃OC(O)(alkyl))₂ are disclosed in U.S. Pat. No. 5,663,159.

Procedures for preparing a derivative comprised of—P(O)(O(CH₂)₁₋₃OC(O)O(alkyl))₂ are disclosed in U.S. Pat. Nos.5,922,695; 5,977,089; and 6,043,230.

Procedures for preparing a derivative comprised of—P(O)(O(CH₂)₁₋₃SC(O)alkyl)₂ are disclosed in U.S. Pat. Nos. 5,770,725;5,849,905; 6,020,482; and 7,105,499.

X. Preparation of 2′-Spiro-Nucleotides

Starting Material

B Product 32

Uracil 135 48

Uracil 136 49

Cytosine 137 50

Cytosine 138 51

Cytosine 139 52

Cytosine 140

The unprotected nucleoside (0.10 mmol) was dissolved in DTP and cooledto 0-5° C. while maintaining an inert atmosphere. To the stirredsolution was added freshly distilled phosphorus oxychloride (0.30 mmol).After 1 h at 0-5° C., tributylamine (0.30 mmol) and freshly driedtributylammonium pyrophosphate (0.25 mmol) were added. The reaction wasallowed to warm to ambient temperature for 1 h and then quenched by theaddition 1.0 M aqueous triethylamine bicarbonate buffer (1 mL). Thereaction solution was directly applied in portions to an ion-exchangeHPLC semi-preparative column (Dionex DNA-PAC) and eluted with a gradientof 0.5 M aqueous triethylammonium bicarbonate in water. The productcontaining fractions were combined and concentrated to dryness. Theresidue was then dissolved in about 5 mL water and then subjected tolyophilization to yield ca 0.01-0.02 mmol of nucleoside triphosphate asits monotriethylamine salt.

XI. Biological Evaluation of Selected Analogs

HCV replicon assay. HCV replicon assays using Clone A cells and ET-lunetcells were performed as described previously. L. J. Stuyver et al.Antimicrob. Agents Chemother. 2004, 48, 651-654. Briefly, Clone A cellsand ET-lunet cells were seeded at a density of 1500 and 3000 cells perwell in a 96-well plate, respectively. Test compounds serially dilutedin culture medium without G418 were added to cells. Plates wereincubated at 37° C. in a 5% CO₂ atmosphere for 4 days. Inhibition of HCVRNA replication was determined by quantitative real time PCR. See, e.g.,L. J. Stuyver et al. Antiviral Chem. Chemother. 2006, 17, 79-87.

To express the antiviral effectiveness of a compound, the thresholdRT-PCR cycle of the test compound was subtracted from the averagethreshold RT-PCR cycle of the no-drug control (ΔCt_(HCV)). A ΔCt of 3.3equals a 1-log 10 reduction (equal to the 90% effective concentration[EC₉₀]) in replicon RNA levels. The cytotoxicity of the test compoundcould also be expressed by calculating the ΔCt_(rRNA) values. The ΔΔCtspecificity parameter could then be introduced (ΔCt_(HCV)-ΔCt_(rRNA)),in which the levels of HCV RNA are normalized for the rRNA levels andcalibrated against the no-drug control.

Cell cytotoxicity assays. Each compound (serially diluted from 100 μM)was added to Huh7 (2×10³ cells/well), HepG2 (2×10³ cells/well), BxPC3(2×10³ cells/well), or CEM (5×10³ cells/well) cells and allowed toincubate for 8 days at 37° C. A medium only control was used todetermine the minimum absorbance value and an untreated cell. At the endof the growth period, MTS dye from the CellTiter 96 Aqueous One SolutionCell Proliferation Assay kit (Promega) was added to each well and theplate was incubated for an additional 2 hours. The absorbance at 490 nmwas read with a Victor3 plate reader (Perkin Elmer) using the mediumonly control wells as blanks. The 50% inhibition value (CC₅₀) wasdetermined by comparing the absorbance in wells containing cells andtest compound to untreated cell control wells.

The HCV NS5B reaction was performed in a 20 μL mixture containingvarying concentrations of the test compound, 1 μM of all four naturalribonucleotides, [α-³²P]UTP, 20 ng/μL of genotype 1b (−) IRES RNAtemplate, 1 unit/μL of SUPERase•In (Ambion, Austin, Tex.), 40 ng/μL ofwild type or S282T NS5B Genotype 1b, 1 mM MgCl₂, 0.75 mM MnCl₂, and 2 mMDTT in 50 mM Hepes buffer (pH 7.5). The reaction was quenched by adding80 μL of stop solution (12.5 mM EDTA, 2.25 M NaCl, and 225 mM sodiumcitrate) after incubating at 27° C. for 30 minutes. The radioactive RNAproducts were separated from unreacted substrates by passing thequenched reaction mixture through a Hybond N+ membrane (GE Healthcare,Piscataway, N.J.) using a dot-blot apparatus. The RNA products wereretained on the membrane and the free nucleotides were washed out. Themembrane was washed 4 times with a solution containing 0.6 M NaCl and 60mM sodium citrate. After rinsing the membrane with water followed byethanol, the membrane was exposed to a phosphorscreen and the productswere visualized and quantified using a phosphorimager. The IC₅₀ valueswere calculated using GraFit program version 5 (Erithacus Software,Horley, Surrey, UK). All the reactions were done in duplicate and theresults were reported as IC₅₀±standard error.

The biological activities of selected compounds are presented in Tables1-5.

TABLE 1 Anti-HCV activity of selected nucleosides EC₅₀ Ex. Compound (μM)32

>100 50

>100 36

>100 51

>100 44

>100 49

>100 48

>100 52

>54.49 62

>20 72

>20 76

>100 77

>20 66

>20

TABLE 2 Anti-HCV 1b activity of selected nucleoside phosphoramidates.Ex. Compound EC₅₀ EC₉₀ CC₅₀ 114

20.61 41.69 >100 115

28.5 71.09 >100 116

28.33 81.75 >100 117

16.71 49.20 >100 113

1.55 7.66 >100

TABLE 3 Anti-HCV 1b activity of selected nucleoside phosphoramidates.EC₅₀ EC₉₀ CC₅₀ Ex. Compound P*^(a) (μM) (μM) (μM) 118

S_(P) 1.49 3.44 >20 119

R_(P) 4.52 >20 >20 120

S_(P) 0.39 0.676 >20 121

R_(P) 9.31 18.5 >20 122

S_(P) 0.857 3.0 >20 123

S_(P)/R_(P) ^(b) 0.31 0.853 >20 124

S_(P) 0.566 1.81 >20 125

R_(P) 4.42 8.45 >20 126

S_(P) 0.274 0.7 >20 127

R_(P) 3.1 6.45 >20 128

S_(P) 0.45 1.09 >20 129

R_(P) 0.67 1.97 >20 130

S_(P) 8.65 15.1 >20 131

R_(P) 11.7 >20 >20 ^(a)Chirality at Phosphorus (P*). ^(b)S_(p)/R_(p) =mixture of diastereomers.

TABLE 4 Anti-HCV 1b activity of selected nucleoside cyclic phosphates P-chirality EC₅₀ EC₉₀ CC₅₀ Example Structure (R_(P)/S_(P)) (μM) (μM) (μM)132 (1:1)

(1:1) >20 >20 >20 133 (3.7:1)

(3.7:1) >20 >20 >20 134 (4.7:1)

(4.7:1) 14.0 >20 >20

TABLE 5 Anti-HCV activity of selected nucleoside triphosphates againstHCV polymerase wild-type and S282T mutant Wild-type S282T mutant ExCompound IC₅₀ (μM) IC₅₀ (μM) 135

>100 136

39.4 >100 137

>45.3 >100 138

>100 139

>100 140

>8.48 56.7

Dengue CPE Assay. To measure cytopathic effect of Dengue virus 2, BHK-21(Syrian Hamster Kidney, CCL-10 ATCC Manassas, Va.) cells were seeded ata density of 20,000 cells/well in a 96-well black/clear bottom plates(Becton Dickinson, Franklin Lakes, N.J.) one day prior to start of theassay and allowed to attach overnight in EMEM (ATCC Manassas, Va.) +10%FBS (Invitrogen, Carlsbad, Calif.) at 37° C. in a humidified 5% CO₂atmosphere. The next day, the medium was removed and the cells wereinfected with Dengue 2 strain New Guinea C (VR-1584, ATCC Manassas, Va.)at an MOI of 0.08 pfu/cell for two hours in 50 μL EMEM+2% FBS. For boththe single point and dose response assays, compounds (2× concentration)were diluted in EMEM+2% FBS and 50 μL was added to infected cellswithout removing virus. Cells were incubated for 3 days at 37° C. in ahumidified 5% CO₂ atmosphere. The medium was aspirated and 50 μL ofCellTiter-Glo (Promega, Madison, Wis.) was added to each well and readfor 0.1 seconds on a Perkin Elmer Victor3 (Waltham, Mass.) plate reader.Percent survival was determined by subtracting the average value ofinfected control wells and normalizing to the non-infected wells. Theeffective concentration was calculated from the dose response data byforecasting 50% cells surviving with drug treatment.

TABLE 6 Activity of selected nucleoside phosphoramidates against denguevirus. EC₅₀ CC₅₀ Ex. Compound P*^(a) (μM) (μM) 113

R_(P)/S_(P) ^(b) 6.23 >20 118

S_(P) 5.06 >20 119

R_(P) 8.64 >20 120

S_(P) 1.88 >20 121

R_(P) 2.26 >20 122

S_(P) 5.84 >20 123

S_(P)/R_(P) ^(b) 1.74 >20 124

S_(P) 2.21 >20 125

R_(P) 1.98 >20 126

S_(P) 2.36 >20 127

R_(P) 1.61 >20 128

S_(P) 2.79 >20 129

R_(P) 2.36 >20 130

S_(P) 3.84 >20 131

R_(P) 1.49 >20 ^(a)Chirality at Phosphorus (P*). ^(b)S_(P)/R_(P) =mixture of diastereomers.

Although a full and complete description is believed to be containedherein, certain patent and non-patent references may include certainessential subject matter. To the extent that these patent and non-patentreferences describe essential subject matter, these references arehereby incorporated by reference in their entirety. It is understoodthat the meanings of the incorporated subject matter are subservient tothe meanings of the subject matter disclosed herein. The subject matterof U.S. 61/417,946, filed on Nov. 30, 2010 is hereby incorporated byreference in its entirety. The subject matter of U.S. Ser. Nos.13/076,552 and 13/076,842, both filed on Mar. 31, 2011, is herebyincorporated by reference in its entirety.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

What is claimed is:
 1. A method of treating a hepatitis C virusinfection in a subject in need thereof, comprising administering to thesubject an effective amount of the compound:

or a stereoisomer, salt, metabolite or deuteride thereof.
 2. The methodof claim 1, wherein the hepatitis C virus is of genotype 1b.
 3. Themethod of claim 1, wherein the compound is administered by suppositoryadministration.
 4. The method of claim 1, wherein the compound isadministered orally.
 5. The method of claim 4, wherein the compound isadministered in the form of a tablet, capsule, solution, emulsion, syrupor a suspension.
 6. The method of claim 4, wherein the compound isadministered at a daily dosage of from about 0.01 gm to about 1 gm. 7.The method of claim 1, wherein the method further comprisesadministering an effective amount of another antiviral agent.
 8. Themethod of claim 7, wherein the another antiviral agent is a NS3 proteaseinhibitor, NS4 inhibitor, NS5A inhibitor or NS5B inhibitor.
 9. Themethod of claim 8, wherein the another antiviral agent is a NS3 proteaseinhibitor.
 10. The method of claim 7, wherein the compound and theanother antiviral agent are formulated in same dosage form or separatedosage forms.
 11. The method of claim 7, wherein the administering ofthe compound and the another antiviral agent is concurrent oralternative.
 12. A method of treating a hepatitis C virus infection in asubject in need thereof, comprising administering to the subject aneffective amount of the compound:

or a stereoisomer, salt, metabolite or deuteride thereof.
 13. The methodof claim 12, wherein the hepatitis C virus is of genotype 1b.
 14. Themethod of claim 12, wherein the compound is administered by suppositoryadministration.
 15. The method of claim 12, wherein the compound isadministered orally.
 16. The method of claim 15, wherein the compound isadministered in the form of a tablet, capsule, solution, emulsion, syrupor a suspension.
 17. The method of claim 15, wherein the compound isadministered at a daily dosage of from about 0.01 gm to about 1 gm. 18.The method of claim 12, wherein the method further comprisesadministering an effective amount of another antiviral agent.
 19. Themethod of claim 18, wherein the another antiviral agent is a NS3protease inhibitor, NS4 inhibitor, NS5A inhibitor or NS5B inhibitor. 20.The method of claim 19, wherein the another antiviral agent is a NS3protease inhibitor.
 21. The method of claim 18, wherein the compound andthe another antiviral agent are formulated in same dosage form orseparate dosage forms.
 22. The method of claim 18, wherein theadministering of the compound and the another antiviral agent isconcurrent or alternative.
 23. A method of treating a dengue virusinfection in a subject in need thereof, comprising administering to thesubject an effective amount of the compound:

or a stereoisomer, salt, metabolite or deuteride thereof.
 24. The methodof claim 23, wherein the compound is administered by suppositoryadministration.
 25. The method of claim 23, wherein the compound isadministered orally.
 26. The method of claim 25, wherein the compound isadministered in the form of a tablet, capsule, solution, emulsion, syrupor a suspension.
 27. The method of claim 25, wherein the compound isadministered at a daily dosage of from about 0.01 gm to about 1 gm. 28.The method of claim 23, wherein the method further comprisesadministering an effective amount of another antiviral agent.
 29. Themethod of claim 28, wherein the compound and the another antiviral agentare formulated in same dosage form or separate dosage forms.
 30. Themethod of claim 28, wherein the administering of the compound and theanother antiviral agent is concurrent or alternative.
 31. A method oftreating a dengue virus infection in a subject in need thereof,comprising administering to the subject an effective amount of thecompound:

or a stereoisomer, salt, metabolite or deuteride thereof.
 32. The methodof claim 31, wherein the compound is administered by suppositoryadministration.
 33. The method of claim 31, wherein the compound isadministered orally.
 34. The method of claim 33, wherein the compound isadministered in the form of a tablet, capsule, solution, emulsion, syrupor a suspension.
 35. The method of claim 33, wherein the compound isadministered at a daily dosage of from about 0.01 gm to about 1 gm. 36.The method of claim 31, wherein the method further comprisesadministering an effective amount of another antiviral agent.
 37. Themethod of claim 36, wherein the compound and the another antiviral agentare formulated in same dosage form or separate dosage forms.
 38. Themethod of claim 36, wherein the administering of the compound and theanother antiviral agent is concurrent or alternative.
 39. A compound offormula:

or a stereoisomer, salt, metabolite or deuteride thereof.
 40. A compoundof formula:

or a stereoisomer, salt, metabolite or deuteride thereof.